Fatty acid transport proteins

ABSTRACT

A family of fatty acid transport proteins (FATPs) mediate transport of long chain fatty acids (LCFAs) across cell membranes into cells. These proteins exhibit different expression patterns among the organs of mammals. Nucleic acids encoding FATPs of this family, vectors comprising these nucleic acids, as well as the production of FATP proteins in host cells are described. Also described are methods to test FATPs for fatty acid transport function, and methods to identify inhibitors or enhancers of transport function. The altering of LCFA uptake by administering to the mammal an inhibitor or enhancer of FATP transport function of a FATP in the small intestine can decrease or increase calories available as fats, and can decrease or increase circulating fatty acids. The organ specificity of FATP distribution can be exploited in methods to direct drugs, diagnostic indicators and so forth to an organ such as the heart.

RELATED APPLICATIONS

[0001] This application is a divisional of U.S. application Ser. No.09/611,197 filed Jul. 6, 2000 which is a continuation-in-part of U.S.patent application Ser. No. 09/506,252 filed Feb. 17, 2000 which is acontinuation-in-part of U.S. patent application Ser. No. 09/465,280filed Dec. 16, 1999, a continuation-in-part of U.S. patent applicationSer. No. 09/405,504 filed Sep. 23, 1999, a continuation-in-part of U.S.patent application Ser. No. 09/405,505 filed Sep. 23, 1999, acontinuation-in-part of U.S. patent application Ser. No. 09/232,197filed Jan. 14, 1999, now U.S. Pat. No. 6,300,096, a continuation-in-partof U.S. patent application Ser. No. 09/232,200 filed Jan. 14, 1999, nowU.S. Pat. No. 6,288,213, a continuation-in-part of U.S. patentapplication Ser. No. 09/232,201 filed Jan. 14, 1999, now U.S. Pat. No.6,348,321, a continuation-in-part of U.S. patent application Ser. No.09/232,195 filed Jan. 14, 1999, a continuation-in-part of U.S. patentapplication Ser. No. 09/232,191 filed Jan. 14, 1999, now U.S. Pat. No.6,284,487, each of which claims the benefit of U.S. ProvisionalApplication No. 60/110,941 filed Dec. 4, 1998; U.S. ProvisionalApplication No. 60/093,491 filed Jul. 20, 1998; and U.S. ProvisionalApplication No. 60/071,374 filed Jan. 15, 1998. The teachings of each ofthese referenced applications are incorporated herein by reference intheir entirety.

GOVERNMENT SUPPORT

[0002] The invention was supported, in whole or in part, by a grant fromthe National Heart, Lung, and Blood Institute (HL41484), by NationalInstitutes of Health Grant DK 47618 and National Institutes of HealthGrant 5 T32 CA 09541. The United States Government has certain rights inthe invention.

BACKGROUND OF THE INVENTION

[0003] Long chain fatty acids (LCFAs) are an important source of energyfor most organisms. They also function as blood hormones, regulating keymetabolic functions such as hepatic glucose production. Although LCFAscan diffuse through the hydrophobic core of the plasma membrane intocells, this nonspecific transport cannot account for the high affinityand specific transport of LCFAs exhibited by cells such as cardiacmuscle, hepatocytes, enterocytes, and adipocytes. The molecularmechanisms of LCFA transport remains largely unknown. Identifying thesemechanisms can lead to pharmaceuticals that modulate fatty acid uptakeby the intestine and by other organs, thereby alleviating certainmedical conditions (e.g. obesity).

SUMMARY OF THE INVENTION

[0004] Described herein is a diverse family of fatty acid transportproteins (FATPs) which are evolutionarily conserved; these FATPs areplasma membrane proteins which mediate transport of LCFAs across themembranes and into cells. Members of the FATP family described hereinare present in a wide variety of organisms, from mycobacteria to humans,and exhibit very different expression patterns in tissues among theorganisms. FATP family members are expressed in prokaryotic andeukaryotic organisms and comprise characteristic amino acid domains orsequences which are highly conserved across family members. In addition,the function of the FATP gene family is conserved throughout evolution,as shown by the fact that the Caenorhabditis (C). elegans andmycobacterial FATPs described herein facilitate LCFA uptake when theyare overexpressed in COS cells or Escherichia(E.) coli, respectively.FATPs are expressed in a wide variety of tissues, including all tissueswhich are important to fatty acid metabolism (uptake and processing).

[0005] In specific embodiments, FATPs of the present invention are fromsuch diverse organisms as humans (Homo (H.) sapiens), mice, (Mus (M.)musculus), F. rubripes, C. elegans, Drosophila (D.) melanogaster,Saccharomyces (S.) cerevisiae, Aspergillus nidulans, Cochlioboluheterostrophus, Magnaporthe grisea and Mycobacterium (M.), such as M.tuberculosis. As described herein, four novel mouse FATPs, referred toas mmFATP2, mmFATP3, mmFATP4 and mmFATP5, and six human FATPs, referredto as hsFATP1, hsFATP2, hsFATP3, hsFATP4, hsFATP5 and hsFATP6, have beenidentified. All four novel murine FATPs (mmFATP2-5) and a previouslyidentified murine FATP (renamed herein FATP1) have orthologs in humans(hsFATP1-5); the sixth human FATP (hsFATP6) does not as yet have a mouseortholog. The expression patterns of these FATPs vary, as described indetail below.

[0006] The present invention relates to FATP family members fromprokaryotes and eukaryotes, nucleic acids (DNA, RNA) encoding FATPs, andnucleic acids which are useful as probes or primers (e.g., for use inhybridization methods, amplification methods) for example, in methods ofdetecting FATP-encoding genes, producing FATPs, and purifying orisolating FATP-encoding DNA or RNA. Also the subject of this inventionare antibodies (polyclonal or monoclonal) which bind an FATP or FATPs;methods of identifying additional FATP family members (for example,orthologs of those FATPs described herein by amino acid sequence) andvariant alleles of known FATP genes; methods of identifying compoundswhich bind to an FATP, or modulate or alter (enhance or inhibit) FATPfunction; compounds which modulate or alter FATP function; methods ofmodulating or altering (enhancing or inhibiting) FATP function and,thus, LCFA uptake into tissues of a mammal (e.g. human) by administeringa compound or molecule (a drug or agent) which increases or reduces FATPactivity; and methods of targeting compounds to tissues by administeringa complex of the compound to be targeted to tissues and a componentwhich is bound by an FATP present on cells of the tissues to which thecompound is to be targeted. For example, a complex of a drug to bedelivered to the liver and a component which is bound by an FATP presenton liver cells (e.g., FATP5) can be administered.

[0007] In one embodiment, the present invention relates to modulating oraltering (enhancing or inhibiting/reducing) LCFA uptake in the smallintestine and, thus, increasing or reducing the number of calories inthe form of fats available to an individual. In another embodiment, thepresent invention relates to inhibiting or reducing LCFA uptake in thesmall intestine in order to reduce circulating fatty acid levels; thatis, LCFA uptake in the small intestine is reduced and, therefore,circulating (blood) levels are not as high as they otherwise would be.FATP4 has been shown to be expressed in epithelial cells of the smallintestine and particularly in the brush border layer of the smallintestine. FATP2 has also been shown to be expressed at low levels inepithelial cells of the small intestine, particularly in the duodenum.In contrast, FATP1, FATP3, FATP5 and FATP6 were not detected in any ofthe intestinal tissues. Thus, also described herein are FATPs which arepresent in the epithelial cell layer of the small intestine where theymediate LCFA uptake. These FATPs, particularly FATP4 and also FATP2, aretargets for methods and drugs which block their function or activity andare useful in treating obesity, diabetes and heart disease. The abilityof these FATPs to mediate fat uptake can be modulated or altered(enhanced or inhibited), thus modulating fat uptake in the smallintestine. This can be done, for example, by administering to anindividual, such as a human or other animal, a drug which blocksinteraction of LCFAs with FATP4 and/or FATP2 in the small intestine,thus inhibiting LCFA passage into the cells of the small intestine. As aresult, fat absorption is reduced and, although the individual hasconsumed a certain quantity of fat, the LCFAs are not absorbed to thesame extent they would have been in the absence of the compoundadministered.

[0008] Thus, one embodiment of this invention is a method of reducingLCFA uptake (absorption) in the small intestine and, as a result,reducing caloric uptake in the form of fat. A further embodiment is acompound (drug) useful in inhibiting or reducing fat absorption in thesmall intestine. In another embodiment, the invention is a method ofreducing circulating fatty acid levels by administering to an individuala compound which blocks interactions of LCFAs with FATP4 and/or FATP2 inthe small intestine, thus inhibiting LCFA passage into cells of thesmall intestine. As a result, fatty acids pass into the circulatorysystem at a diminished level and/or rate, and circulating fatty acidlevels are lower than they would be in the absence of the compoundadministered. This method is particularly useful for therapy inindividuals who are at risk for or have hyperlipidemia. That is, it canbe used to prevent the occurrence of elevated levels of lipids in theblood or to treat an individual in whom blood lipid levels are elevated.Also the subject of this invention is a method of identifying compoundswhich alter FATP function (and thus, in the case of FATP2 and/or FATP4,alter LCFA uptake in the small intestine).

[0009] In another embodiment, the present invention relates to a methodof modulating or altering (enhancing or inhibiting) the function ofFATP6, which is expressed at high levels in the heart. A method ofinhibiting FATP6 function is useful, for example, in individuals withheart disease, such as ischemia, since reducing LCFA uptake into heartmuscle in an individual who has ischemic heart disease, which may bemanifested by, for example, angina or heart attack, can reduce symptomsor reduce the extent of damage caused by the ischemia. In thisembodiment, a drug which inhibits FATP6 function is administered to anindividual who has had or is having a heart attack, to reduce LCFAuptake by the individual's heart and, as a result, reduce the damagecaused by ischemia. In a further embodiment, this invention is a methodof targeting a compound, such as a therapeutic drug or an imagingreagent, to heart tissue by administering to an individual (e.g., ahuman) a complex of the compound and a component (e.g., a LCFA orLCFA-like compound) which is bound by an FATP (e.g., FATP6) present incells of heart tissue.

[0010] In a further embodiment, LCFA uptake by the liver is modulated oraltered (enhanced or reduced), in an individual. For example, a drugwhich inhibits the function of an FATP present in liver (e.g., FATP5) isadministered to an individual who is diabetic, in order to reduce LCFAuptake by liver cells and, thus reduce insulin resistance.

[0011] The present invention, thus, provides methods which are useful toalter, particularly reduce, LCFA uptake in individuals and, as a result,to alter (particularly reduce), availability of the LCFAs for furthermetabolism. In a specific embodiment, the present invention providesmethods useful to reduce LCFA uptake and, thus, fatty acid metabolism inindividuals, with the result that caloric availability from fats isreduced, and circulating fatty acid levels are lower than they otherwisewould be. These methods are useful, for example, as a means of weightcontrol in individuals, (e.g., humans) and as a means of preventingelevated serum lipid levels or reducing serum lipid levels in humans.FATPs expressed in the small intestine, such as FATP4, are usefultargets to be blocked in treating obesity (e.g., chronic obesity) or tobe enhanced in treating conditions in which enhanced LCFA uptake isdesired (e.g., malabsorption syndrome or other wasting conditions).

[0012] The identification of this evolutionarily conserved fatty acidtransporter family will allow a better understanding of the mechanismswhereby LCFAs traverse the lipid bilayer as well as yield insight intothe control of energy homeostasis and its dysregulation in diseases suchas diabetes and obesity.

BRIEF DESCRIPTION OF THE DRAWINGS

[0013] The file of this patent contains at least one color photograph.Copies of this patent with color photographs will be provided by thePatent and Trademark Office upon request and payment of necessary fee.

[0014]FIG. 1 shows the amino acid sequence alignment of FATPs: mmFATP1(SEQ ID NO:92), mmFATP2 (SEQ ID NO:93), mmFATP3 (SEQ ID NO:94), mmFATP4(SEQ ID NO:95), mmFATP5 (SEQ ID NO:96), ceFATPa (SEQ ID NO:97), scFATP(SEQ ID NO:98) and mtFATP (SEQ ID NO:99). The underlining (amino acidresidues 204-212 of mtFATP) indicates an AMP binding motif which isfound in many classes of proteins; the underlining at amino acidresidues 204-507 of the mtFATP sequence indicates the FATP 360 aminoacid signature sequence.

[0015] FIGS. 2A-2D show results of LCFA uptake assays. FIGS. 2A-2D: COScells were cotransfected using the DEAE-dextran method with themammalian expression vectors pCDNA-CD2 either alone (control; FIG. 2A)or in combination with one of the FATP-containing expression vectors(pCDNA-mmFATP1, FIG. 2B; pCDNA-mmFATP2, FIG. 2C; or pCMV-SPORT2-mmFATP5,FIG. 2D) as described in Materials and Methods for Example 2. COS cellswere gated on forward scatter (FSC) and side scatter (SS), and theresults shown represent >10,000 cells. Cells exhibiting >300 CD2fluorescence units (vertical line) representing 15% of all cells weredeemed CD2 positive.

[0016]FIG. 3 is a graph of fluorescence of cells expressing a FATP gene.As in FIGS. 2A-2D, COS cells were cotransfected with pCDNA-CD2 eitheralone (control) or in combination with one of the FATP-containingexpression vectors (pCDNA-mmFATP1, pCDNA-mmFATP2, pCMV-SPORT2-mmFATP5,or pCDNA-ceFATPb). The mean BODIPY-FA fluorescence of the CD2-positivecells is plotted; results shown represent the average of threeexperiments, each consisting of greater than 50,000 COS cells. Note thata logarithmic scale is used on the ordinate.

[0017]FIG. 4 is a graph of the uptake of palmitate with time. Thefull-length coding region of mtFATP (squares) or a control protein(TFE3; circles) was subcloned into the inducible, prokaryotic expressionvector pET (Novagen, Madison, Wis.). Expression from the resultingplasmid was induced (solid symbols) in transformed E. coli cells with 1mM isopropyl-β-D-thiogalactoside (IPTG) for 1 hour, or cells were leftuninduced (open symbols). Data points were done in triplicate and countswere normalized to the number of bacteria as determined by OD₆₀₀.

[0018]FIG. 5 is a phylogenetic tree produced by aligning complete andpartial sequences for FATP genes from human, rat, mouse, puffer fish, D.melanogaster, C. elegans, S. cerevisiae, and M. tuberculosis usingClustalX and using these data to produce a phylogenetic tree usingTreeViewPPC. The bar indicates the number of substitutions per residue,i.e., 0.1 corresponds to a distance of 10 substitutions per 100residues.

[0019]FIG. 6 shows a comparison of the FATP signature sequences ofmmFATP1 (SEQ ID NO:1), mmFATP5, (SEQ ID NO:2), ceFATPa (SEQ ID NO:3),scFATP (SEQ ID NO:4) and mtFATP (SEQ ID NO:5).

[0020]FIG. 7 shows the sequence identity among the FATP family membersand VLACs, based on the 360 amino acid signature sequence of FATP fromFIG. 1.

[0021]FIGS. 8A and 8B are the mmFATP3 DNA sequence (SEQ ID NO:6).

[0022]FIG. 9 is the mmFATP3 protein sequence (SEQ ID NO:7).

[0023]FIGS. 10A and 10B are the mmFATP4 DNA sequence (SEQ ID NO:8).

[0024]FIG. 11 is the mmFATP4 protein sequence (SEQ ID NO:9).

[0025]FIGS. 12A and 12B are the mmFATP5 DNA sequence (SEQ ID NO:10).

[0026]FIG. 13 is the mmFATP5 protein sequence (SEQ ID NO:11).

[0027]FIGS. 14A and 14B are the hsFATP2 DNA sequence (SEQ ID NO:12).

[0028]FIG. 15 is the hsFATP2 protein sequence (SEQ ID NO:13).

[0029]FIGS. 16A and 16B are the hsFATP3 DNA sequence (SEQ ID NO:14).

[0030]FIG. 17 is the hsFATP3 protein sequence (SEQ ID NO:15).

[0031]FIGS. 18A and 18B are the hsFATP4 DNA sequence (SEQ ID NO:16).

[0032]FIG. 19 is the hsFATP4 protein sequence (SEQ ID NO:17).

[0033]FIGS. 20A and 20B are the hsFATP5 DNA sequence (SEQ ID NO:18).

[0034]FIG. 21 is the hsFATP5 protein sequence (SEQ ID NO:19).

[0035]FIGS. 22A and 22B are the hsFATP6 DNA sequence (SEQ ID NO:20).

[0036]FIG. 23 is the hsFATP6 protein sequence (SEQ ID NO:21).

[0037]FIGS. 24A and 24B are the mtFATP DNA sequence (SEQ ID NO:22).

[0038]FIG. 25 is the mtFATP protein sequence (SEQ ID NO:23).

[0039]FIG. 26 shows the DNA sequence (SEQ ID NO:24) and predicted aminoacid sequence (SEQ ID NO:25) of human FATP1.

[0040]FIG. 27 shows the DNA sequence (SEQ ID NO:26) and predicted aminoacid sequence (SEQ ID NO:27) of human FATP4.

[0041]FIG. 28A is a hydrophobicity plot for hsFATP1, showing that it hasmultiple membrane-spanning domains.

[0042]FIG. 28B is the amino acid composition of hsFATP1.

[0043]FIG. 28C is a hydrophilicity plot for hsFATP 1, made using theKyte-Doolittle method, averaging hydrophilicity values for 18 amino acidresidues at a time.

[0044]FIG. 29A is a hydrophobicity plot for hsFATP4, showing that it hasmultiple membrane-spanning domains.

[0045]FIG. 29B is a listing of the amino acid composition of hsFATP4.

[0046]FIG. 29C is a hydrophilicity plot for hsFATP4, made using theKyte-Doolittle method, averaging hydrophilicity values for 18 amino acidresidues at a time.

[0047]FIGS. 30A and 30B show a comparison of the nucleotide sequence ofhuman FATP1 (SEQ ID NO:28) and the nucleotide sequence of mouse FATP1(SEQ ID NO:29).

[0048]FIGS. 31A and 31B show a comparison of the nucleotide sequence ofhuman FATP4 (SEQ ID NO:30) and the nucleotide sequence of mouse FATP4(SEQ ID NO:31).

[0049]FIG. 32 shows a comparison of the amino acid sequence of humanFATP1 (SEQ ID NO:32) and the amino acid sequence of mouse FATP1 (SEQ IDNO:33). Shaded amino acid residues match the consensus sequence exactly.

[0050]FIG. 33 shows a comparison at the amino acid level of human FATP4(SEQ ID NO:34) and mouse FATP4 (SEQ ID NO:35). Shaded amino acidresidues match the consensus sequence exactly.

[0051]FIG. 34 shows the nucleotide sequence (SEQ ID NO:36) and predictedamino acid sequence (SEQ ID NO:37) of hsFATP6.

[0052]FIG. 35A is a hydrophobicity plot for hsFATP6, showing that it hasmultiple membrane-spanning domains.

[0053]FIG. 35B is a listing of the amino acid composition of hsFATP6.

[0054]FIG. 35C is a hydrophilicity plot for hsFATP6, made using theKyte-Doolittle method, averaging hydrophilicity values for 18 amino acidresidues at a time.

[0055]FIG. 36 shows an alignment of the amino acid sequences of hsFATP1(SEQ ID NO:38), hsFATP4 (SEQ ID NO:39) and hsFATP6 (SEQ ID NO:40).Shaded amino acid residues match the consensus sequence exactly.

[0056]FIG. 37 shows results of assessment of fatty acid uptake by humanFATP1 and human FATP4. The percent of CD2-positive cells exhibiting aBODIPY-fluorescence of more than 300 arbitrary units is plotted for thethree different conditions tested.

[0057]FIG. 38 is a graph showing uptake of tritiated oleate, with time,by 293 cells transfected with either (diamonds) a plasmid for expressionof human FATP4 or (squares) a control plasmid.

[0058]FIG. 39 is an illustration of the amino acid sequences of humanFATP4 (SEQ ID NO:41) and mouse FATP4 (SEQ ID NO:42) compared to humanFATP1 (SEQ ID NO:43). Shown by underlining are the FATP consensussequence (236-556 of hsFATP1) and the AMP-binding motif (246-254 ofhsFATP1). The human FATPs were cloned by screening libraries withsequences from ESTs (expressed sequence tags). Mouse FATP4 was cloned byPCR using degenerate primers.

[0059]FIG. 40 is a graph showing the uptake, with time, of tritiatedoleate by mouse enterocytes in the presence of no oligonucleotide(squares), sense oligonucleotide (circles) or antisense oligonucleotide(diamonds).

[0060]FIG. 41 is a bar graph showing uptake of tritiated oleate, bymouse enterocytes in the presence of various concentrations of antisense(solid bars), mismatch (stippled bars) or sense (lined bars)oligonucleotides.

[0061]FIG. 42 is a bar graph showing uptake of tritiated oleate anduptake of ³⁵S-labeled methionine by mouse enterocytes to which wereadded no oligonucleotide, the antisense oligonucleotide, or the mismatcholigonucleotide.

[0062]FIG. 43A is the nucleotide sequence of the gene encoding mouseFATP4 (SEQ ID NO:44).

[0063]FIG. 43B is the amino acid sequence of mouse FATP4 protein (SEQ IDNO:45).

[0064]FIGS. 44A, 44B, and 44C are the hsFATP1 DNA sequence (SEQ IDNO:46). Coding region: 175-2115 (1941 nt).

[0065]FIG. 45 is the hsFATP1 protein sequence (SEQ ID NO:47).

[0066]FIGS. 46A and 46B are the hsFATP2 DNA sequence (SEQ ID NO:48).Coding region: 223-2085 (1863 nt).

[0067]FIG. 47 is the hsFATP2 protein sequence (SEQ ID NO:49).

[0068]FIG. 48 is the partial DNA sequence of hsFATP3 (SEQ ID NO:50).Coding region: 1-993.

[0069]FIG. 49 is the partial protein sequence of hsFATP3 (SEQ ID NO:51).

[0070]FIGS. 50A, 50B, and 50C are the hsFATP4 DNA sequence (SEQ IDNO:52). Coding region: 208-2139 (1932 nt).

[0071]FIG. 51 is the hsFATP4 protein sequence (SEQ ID NO:53).

[0072]FIG. 52 is the hsFATP5 partial DNA sequence (SEQ ID NO:54). Codingregion: 1-1062.

[0073]FIG. 53 is the hsFATP5 partial protein sequence (SEQ ID NO:55).

[0074]FIGS. 54A, 54B, and 54C are the hsFATP6 DNA sequence (SEQ IDNO:56). Coding region: 643-2502 (1860 nt).

[0075]FIG. 55 is the hsFATP6 protein sequence (SEQ ID NO:57).

[0076]FIGS. 56A, 56B, and 56C are the rnFATP1 DNA sequence (rn=Rattusnorvegicus; (SEQ ID NO:58). Coding region: 75-2015 (1941 nt).

[0077]FIG. 57 is the rnFATP1 protein sequence (SEQ ID NO:59).

[0078]FIGS. 58A, 58B, and 58C are the rnFATP2 DNA sequence (SEQ IDNO:60). Coding region: 795-2657 (1863 nt).

[0079]FIG. 59 is the rnFATP2 protein sequence (SEQ ID NO:61).

[0080]FIGS. 60A and 60B are the mFATP4 partial DNA sequence (SEQ IDNO:62). Coding region: 1-1218.

[0081]FIG. 61 is the rnFATP4 partial DNA sequence (SEQ ID NO:63).

[0082]FIGS. 62A, 62B, and 62C are the mmFATP1 DNA sequence (SEQ IDNO:64). Coding region: 1-1944.

[0083]FIG. 63 is the mmFATP1 protein sequence (SEQ ID NO:65).

[0084]FIGS. 64A and 64B are the mmFATP2 DNA sequence (SEQ ID NO:66).Coding region: 121-1992 (1872 nt).

[0085]FIG. 65 is the mmFATP2 protein sequence (SEQ ID NO:67).

[0086]FIGS. 66A and 66B are the mmFATP3 partial DNA sequence (SEQ IDNO:68). Coding region: 1-1830.

[0087]FIG. 67 is the mmFATP3 partial protein sequence (SEQ ID NO:69).

[0088]FIGS. 68A, 68B, and 68C are the mmFATP4 DNA sequence (SEQ IDNO:70). Coding region: 1-1932.

[0089]FIG. 69 is the mmFATP4 protein sequence (SEQ ID NO:71).

[0090]FIGS. 70A and 70B are the mmFATP5 DNA sequence (SEQ ID NO:72).Coding region: 60-2129.

[0091]FIG. 71 is the mmFATP5 protein sequence (SEQ ID NO:73).

[0092]FIGS. 72A and 72B are the dmFATP partial DNA sequence(dm=Drosophila melanogaster; SEQ ID NO:74). Coding region: 1-1773.

[0093]FIG. 73 is the dmFATP partial protein sequence (SEQ ID NO:75).

[0094]FIG. 74 is the drFATP partial DNA sequence (dr=Danio rerio,zebrafish; SEQ ID NO:76) Coding region: 1-173.

[0095]FIG. 75 is the drFATP partial protein sequence (SEQ ID NO:77).

[0096]FIGS. 76A and 76B are the ceFATPa DNA sequence (SEQ ID NO:78).Coding region: 1-1953.

[0097]FIG. 77 is the ceFATPa protein sequence (SEQ ID NO:79).

[0098]FIGS. 78A and 78B are the ceFATPb DNA sequence (SEQ ID NO:80).Coding region: 1-1968.

[0099]FIG. 79 is the ceFATPb protein sequence (SEQ ID NO:81).

[0100]FIGS. 80A and 80B are the chFATP DNA sequence (SEQ ID NO:82;ch=Cochliobolu heterostrophus). Coding region: 1-1932.

[0101]FIG. 81 is the chFATP protein sequence (SEQ ID NO:83).

[0102]FIG. 82 is the anFATP partial protein sequence (an=Aspergillusnidulans; SEQ ID NO:84). Coding region: 1-597.

[0103]FIG. 83 is the anFATP partial protein sequence (SEQ ID NO:85).

[0104]FIG. 84 is the mgFATP partial DNA sequence (mg=Magnaporthe grisea,rice blast; SEQ ID NO:86). Coding region: 1-522.

[0105]FIG. 85 is the mgFATP partial protein sequence (SEQ ID NO:87).

[0106]FIGS. 86A and 86B are the scFATP DNA sequence (SEQ ID NO:88).Coding region: 1-1872.

[0107]FIG. 87 is the scFATP protein sequence (SEQ ID NO:89).

[0108]FIGS. 88A and 88B are the mtFATP DNA sequence (SEQ ID NO:90).

[0109]FIG. 89 is the mtFATP protein sequence (SEQ ID NO:91). Codingregion: 1-1794.

[0110]FIG. 90 is a consensus sequence of the FATP signature sequence(SEQ ID NO:100), based on 23 independent sequences aligned in ClustalX.The height of the bar at each amino acid residue position indicates thedegree of conservation at that position. Gaps have been inserted tomaintain the strength of the alignment.

[0111]FIG. 91 is a hydrophilicity plot for hsFATP2, made using theKyte-Doolittle method, averaging hydrophilicity values for 18 amino acidresidues at a time.

[0112]FIG. 92 is a hydrophilicity plot for the hsFATP3 partial protein,made using the Kyte-Doolittle method, averaging hydrophilicity valuesfor 18 amino acid residues at a time.

[0113]FIG. 93 is a hydrophilicity plot for the hsFATP5 partial protein,made using the Kyte-Doolittle method, averaging hydrophilicity valuesfor 18 amino acid residues at a time.

[0114]FIGS. 94A and 94B are a representation of the DNA sequence (SEQ IDNO:101) of the hsFATP3 gene, and the amino acid sequence (SEQ ID NO:102)of the hsFATP3 protein.

[0115]FIG. 95 shows that mammalian expression constructs containingeither hsFATP4 (squares and triangles) or empty control vector (circles)were stably transfected into 293 cells. Short-term uptake of Bodipy-FAin the presence of BSA was determined by FACS. The mean fluorescence ofthe viable cell population is expressed in arbitrary fluorescence units.FATP4 protein expression was determined by densitometry of anti-FATP4Western blots, and is expressed in arbitrary units.

[0116]FIG. 96 is a bar graph illustrating short-term uptake ofBodipy-palmitate (1 μM), either by control cells (black bars) orFATP4-expressing cells (hatched bars), was measured in the presence of0, 10, 100 μM unlabeled palmitate. FA uptake was quantified by FACS andexpressed in arbitrary fluorescence units.

[0117]FIG. 97 shows the rate of [²H]palmitate uptake by 293 cells, whichwere stably transfected with a construct for either human FATP4(diamonds) or an empty vector (circles), compared to that of isolatedenterocytes (squares).

[0118]FIG. 98 is a bar graph illustrating the results when isolatedenterocytes were incubated for 48 h with increasing concentrations ofthe FATP4 antisense oligonucleotide or with 100 μM of a randomizedcontrol oligonucleotide with identical nucleotide composition to theFATP4 antisense oligonucleotide. The uptake of oleate by the enterocyteswas then measured over a 5 min time interval (solid bars). In parallel,the levels of FATP4 protein and, as a loading control, β-catenin, weredetermined by Western blotting and quantitated using densitometry(hatched bars). FA uptake and FATP4 protein levels were normalized tothat of untreated cells. The averages and standard deviations of 4independent experiments are shown.

[0119]FIG. 99 is a bar graph illustrating the uptake rates of[³H]oleate, [³H]palmitate and [³⁵S]methionine by primary enterocyteswere measured after 48 h incubation with either 100 μM FATP4 antisense(solid bars) or 100 μM randomized control oligonucleotide (hatched bars)and expressed as % of untreated cells.

[0120]FIG. 100 is a bar graph illustrating that 8 kb of FATP5 genomicsequence SEQ ID NO.: 106 is sufficient for liver specific transcriptionin vitro. A luciferase reporter construct containing 8 kb upstream ofthe FATP5 initiator methionine was transfected into various cell linesusing calcium phosphate as described in Example 17. Forty-eight hoursafter transfection, luciferase activity was measured and normalized toβ-galactosidase activity. For each cell line, fold induction wasdetermined by dividing the relative luciferase activity of the 8 kbconstruct by that of the promoter-less luciferase reporter vector. Thedata shown represent the mean of three experiments done in triplicate.Error bars indicate the SEM.

[0121]FIG. 101 is a bar graph illustrating deletion analysis of theFATP5 promoter. Constructs containing deletions of the FATP5 promoterwere transfected into HepG2 cells, assayed for luciferase activity, andnormalized to β-galactosidase (RLU). The labels on the vertical axiscorrespond to the length of the promoter segment as measured from theinitiator methionine. The data shown represents the mean of threeexperiments done in triplicate. Error bars indicate the SEM.

[0122]FIG. 102 is a bar graph illustrating that 271 base pairs upstreamof the FATP5 initiator methionine are sufficient for liver specificluciferase activity. A luciferase reporter construct containing 271 basepairs upstream of the FATP5 initiator methionine was transfected intovarious cell lines using calcium phosphate as described in MethodsExample 17. Forty eight hours after transfection, luciferase activitywas measured and normalized to β-galactosidase activity. For each cellline, fold induction was determined by dividing the relative luciferaseactivity of the −271 base pair construct by that of the promoter-lessluciferase reporter vector. The data shown represent the mean of threeexperiments done in triplicate. Error bars indicate the SEM.

[0123]FIGS. 103A and 103B illustrate mutations of the GC box whichabolish transcriptional activity. A: Schematic of mutations in the GCbox aligned with the normal sequence (SEQ ID NO.: 106, SEQ ID NO.: 107,SEQ ID NO.: 108). The GC box consensus sequence is underlined. B:Constructs containing 271 base pairs upstream of the FATP5 initiatormethionine with the mutations in the GC box depicted in part A weretransfected into HepG2 cells, assayed for luciferase activity, andnormalized to -galactosidase (RLU). The data shown represent the mean ofthree experiments done in triplicate. Error bars indicate the SEM.

[0124]FIG. 104 shows a gel shift analysis of the GC box with HepG2nuclear extracts. Schematic showing the sequence of the oligonucleotidesused in gel shift studies. The numbering reflects the distance from theinitiator methionine. The two pairs of oligonucleotides are indicated bythe lines and labeled AF-1 (SEQ ID NO.: 111, SEQ ID NO.: 112) and AF-2(SEQ ID NO.: 109, SEQ ID NO.: 110).

[0125]FIG. 105 is a bar graph illustrating that 30 bp internal deletionsof the FATP5 promoter identify another region required for luciferaseactivity in HepG2 cells. Reporter constructs were transfected into HepG2cells. Luciferase activity was measured and normalized toβ-galactosidase activity (RLU). The labels on the horizontal axiscorrespond to the nucleotides that were deleted and the numbering on thevertical axis represents the distance from the initiator methionine. Thedata shown represent the mean of three experiments done in triplicate.Error bars indicate the SEM. Note that the five fold higher RLU activityin this figure relative to FIGS. 101 and 103 is the result of amanufacturer change in the β-galactosidase reagent.

[0126]FIG. 106 is a bar graph illustrating that a linker scan of theFATP5 promoter identifies two additional elements required fortranscription in HepG2 cells. Reporter constructs were transfected intoHepG2 cells. Luciferase activity was measured and normalized toβ-galactosidase activity (RLU). The labels on the horizontal axiscorrespond to the constructs in part A. The data shown represent themean of three experiments done in triplicate. Error bars indicate theSEM. Please note that the lower RLU activity in this figure relative toFIGS. 101 and 103 is also the result of a manufacturer change in theβ-galactosidase reagent.

[0127]FIG. 107 is a schematic of the FATP5 promoter (SEQ ID NO.: 113).The GC box and two motifs identified in the linker scan are boxed andlabeled. An arrow indicates the translational initiator of the FATP5protein. The two halves of the palindrome contained in the novel motifsand referred to in the discussion are underlined.

[0128]FIG. 108 is a photograph showing FATP2 expression in the mousegall bladder epithelium.

[0129]FIG. 109 is a photograph showing FATP2 expression in chimpanzeeliver.

[0130]FIG. 110 is a photograph showing FATP5 expression in chimpanzeeliver.

[0131]FIGS. 111A and 111B represent the DNA sequence (SEQ ID NO:116) ofhuman FATP3.

[0132]FIG. 112 represents the amino acid sequence (SEQ ID NO:1 17) ofhuman FATP3.

[0133]FIG. 113 is a bar graph showing the results of an experimentcomparing fatty acid transport between cells transfected with SEQ IDNO:116 and untransfected cells.

[0134]FIGS. 114A, 114B, 114C and 114D represent portions of the aminoacid sequence of mmFATP4 which were produced as fusion polypeptides inE. coli cells.

[0135]FIG. 115 is a schematic illustrating certain components of thefusion polypeptides depicted in FIGS. 114A-D. The schematic shows thelipocalin domain as well as other identified motifs and notes therelative location of each in the mmFATP4 fusion polypeptide.

[0136]FIG. 116 is a bar graph illustrating the results of an experimentcomparing the binding capabilities of the fusion polypeptides shown inFIGS. 114A-D for an oleate fatty acid.

[0137]FIG. 117 is a bar graph showing the results of an experimentcomparing binding of various fatty acids between two of the fusionpolypeptides depicted in FIGS. 114A-D.

[0138] FIGS. 118A-G illustrates the consensus sequence of hsFATP1,hsFATP2, hsFATP3, hsFATP4, hsFATP5 and hsFATP6 with the lipocalin domainand AMP-binding domain of each noted.

[0139] The foregoing and other objects, features and advantages of theinvention will be apparent from the following more particulardescription of preferred embodiments of the invention, as illustrated inthe accompanying drawings in which like reference characters refer tothe same parts throughout the different views. The drawings are notnecessarily to scale, emphasis instead being placed upon illustratingthe principles of the invention.

DETAILED DESCRIPTION OF THE INVENTION

[0140] As described herein, FATPs are a large evolutionarily conservedfamily of proteins that mediate the transport of LCFAs into cells. Thefamily includes proteins which are conserved from mycobacteria to humansand exhibit very different expression patterns in tissues. Specificembodiments described include FATPs from mice, humans, nematodes, fungiand mycobacteria which have been shown to be functional LCFAtransporters. The term “fatty acid transport proteins” (“FATPs”) as usedherein, refers to the proteins described herein as FATP1, FATP2, FATP3,FATP4, FATP5 and FATP6, which have been described in one or more speciesof mammals, as well as mtFATP, ceFATP, scFATP, anFATP, mgFATP, andchFATP, and other proteins sharing at least about 50% amino acidsequence similarity, preferably at least about 60% sequence similarity,more preferably at least about 70% sequence similarity, and still morepreferably, at least about 80% sequence similarity, and most preferably,at least about 90% sequence similarity in the approximately 360 aminoacid signature sequence. The approximately 360 amino acid FATP signaturesequence is shown in FIG. 1. The consensus sequence of the signaturesequence is shown in FIG. 90. The nomenclature used herein to refer toFATPs includes a species-specific prefix (e.g., mm, Mus musculus; hs orh, Homo sapiens or human; mt M. tuberculosis; dm, D. melanogaster; ce,C. elegans; sc, Saccharomyces cerevisiae) and a number such thatmammalian homologues in different species share the same number. Forexample, six human and five mouse FATP genes which are expressed in avariety of tissues are described herein and are referred to,respectively, as hsFATP1-hsFATP6 and mmFATP1-mmFATP5; for example,hsFATP4 and mmFATP4 are the human and mouse orthologs.

[0141] Expression patterns of human and mouse FATPs have been assessedand are described below. Briefly, results of these assessments show thatFATP5 is a liver-specific gene. FATP2 is highly expressed in liver,kidney and gall bladder epithelium. Both of these proteins, as well asFATP4 and FATPs from nematodes and mycobacteria, have been shown to befunctional LCFA transporters. Results have also shown that FATP4 mRNA ispresent at high levels in epithelial cells of two regions of the smallintestine (the jejunum and ileum) and at lower, but significant, levelsin a third region (the duodenum). They further showed that FATP2 mRNA ispresent in epithelial cells of the duodenum at a level similar to thatof FATP4 mRNA levels, but is present at lower levels in the jejunum andileum. FATP4 mRNA was absent from other cell types of the smallintestine and no FATP4 mRNA could be detected in any cells of the colon.No signals above background could be detected for FATP 1, FATP3 andFATP5 in any of the intestinal tissues. Thus, FATP4 is the major FATP inthe mouse small intestine, which supports a major role for FATP4 (alongwith FATP2 to a lesser extent) in absorption of free fatty acids.hsFATP4 was clearly expressed in the jejunum and ileum; expression wasabsent in the stomach. This, too, is consistent with a major role forFATP4 in absorption of fatty acids in the human gut. Analysis of FATPexpression in human tissues, also described in detail below, showed thathsFATP6, which has no mouse ortholog as yet, is expressed at high levelsin the heart and at low levels in the placenta, but is undetectable inthe other tissues assessed (Example 9). This is consistent with a majorrole for FATP6 in absorption of fatty acids in the heart.

[0142] Analysis of FATP3 expression in murine tissues, also described indetail below, showed that expression occurs at detectable levels inliver, spleen, heart, kidney, testis, white adipose tissue, exocrine andendocrine pancreatic cells, and also in lung tissues. FATP3 is expressedat high levels in type-II pneumocytes, a cell type noted for secretion asurfactant, a phospholipid-rich film critical for lung function (Example19).

[0143] Long chain fatty acids (LCFAs) are an important energy source forpro- and eukaryotes and are involved in diverse cellular processes, suchas membrane synthesis, intracellular signaling, protein modification,and transcriptional regulation. In developed Western countries, humandietary lipids are mainly di- and triglycerides and account forapproximately 40% of caloric intake (Weisburger, J. H. (1997) J. Am.Diet. Assoc. 97:S16-S23). These lipids are broken down into fatty acidsand glycerol by pancreatic lipases in the small intestine (Chapus, C.,Rovery, M., Sarda, L & Verger, R. (1988) Biochimie 70:1223-34); LCFAsare then transported into brush border cells, where the majority isre-esterified and secreted into the lymphatic system as chylomicrons(Green, P. H. & Riley, J. W. (1981) Aust. N.Z.J. Med. 11:84-90). Fattyacids are liberated from lipoproteins by the enzyme lipoprotein lipase,which is bound to the luminal side of endothelial cells (Scow, R. O. &Blachette-Mackie, E. J. (1992) Mol. Cell. Biochem 116:181-191). “Free”fatty acids in the circulation are bound to serum albumin (Spector, A.A. (1984) Clin. Physiol. Biochem 2:123-134) and are rapidly incorporatedby adipocytes, hepatocytes, and cardiac muscle cells. The latter derive60-90% of their energy through the oxidation of LCFAs (Neely, J. F.Rovetto, M. J. & Oram, J. F. (1972) Prog. Cardiovasc. Dis: 15:289-329).Although saturable and specific uptake of LCFAs has been demonstratedfor intestinal cells, hepatocytes, cardiac myocytes, and adipocytes, themolecular mechanisms of LCFA transport across the plasma membrane haveremained controversial (Hui, T. Y. & Bernlohr, D. A. (1997) Front.Biosci. 15:d222-3 1-d231; Schaffer, J. E. & Lodish, H. F, (1995) TrendsCardiovasc. Med. 5:218-224). Described herein is a large family ofhighly homologous mammalian LCFA transporters which show wideexpression, including in all tissues relevant to fatty acid metabolism.Further described are novel members of this family in other species,including mycobacterial and nematode FATPs which, like their mammaliancounterparts, are functional fatty acid transporters.

[0144] The discovery of a diverse but highly homologous family of FATPsis reminiscent of the glucose transporter family. In a manner similar tothe FATPs, the glucose transporters have very divergent patterns oftissue expression (McGowan, K. M., Long, S. D. & Pekala, P. H. (1995)Pharmacol. Ther. 66:465-505). The FATPs, like glucose transporters, mayalso differ in their substrate specificities, uptake kinetics, andhormonal regulation (Thorens, B. (1996) Am. J. Physiol. 270:G541-G553).Indeed, the levels of fatty acids in the blood, like those of glucose,can be regulated by insulin and are dysregulated in diseases such asnoninsulin-dependent diabetes and obesity (Boden, G. (1997) Diabetes46:3-10). The underlying mechanisms for the regulation of free fattyacid concentrations in the blood are not understood, but could beexplained by hormonal modulation of FATPs.

[0145] Insulin-resistance is thought to be the major defect in noninsulin-dependent diabetes mellitus (NIDDM) and is one of the earliestmanifestations of NIDDM (McGarry (1992) Science 258:766-770). Free fattyacids (FFAs) may provide an explanation for why obesity is a risk factorfor NIDDM. Plasma levels of FFAs are elevated in diabetic patients(Reaven et al. (1988) Diabetes 37:1020). Elevated plasma free fattyacids (FFAs) have been demonstrated to induce insulin-resistance inwhole animals and humans (Boden (1998) Front. Biosci. 3:D169-D175). Thisinsulin-resistance is likely mediated by effects of FFAs on a variety ofissues. FFAs added to adipocytes in vitro induce insulin resistance inthis cell type as evidenced by inhibition of insulin-induced glucosetransport (Van Epps-Fung et al. (1997) Endocrinology 138:4338-4345).Rats fed a high fat diet developed skeletal muscle insulin resistance asevidenced by a decrease in insulin-induced glucose uptake by skeletalmuscle (Han et al., (1997) Diabetes 46:1761-1767). In addition, elevatedplasma FFAs increase insulin-suppressed endogenous glucose production inthe liver (Boden (1998) Front. Biosci. 3:D169-D175), thus increasinghepatic glucose output. It has been postulated that the adverse effectsof plasma free fatty acids are due to the FFAs being taken up into thecell, leading to an increase in intracellular long chain fatty acyl.CoA; intracellular long chain acyl CoAs are thought to mediate theeffects of FFAs inside the cell. Thus, fatty acid inducedinsulin-resistance may be prevented by blocking uptake of FFAs intoselect tissues, in particular liver (by blocking FATP2 and/or FATP5),adipocyte (by blocking FATP1), and skeletal muscle (by blocking FATP1).Blocking intestinal fat absorption (by blocking FATP4) is also expectedto reduce plasma FFA levels and thus improve insulin resistance.

[0146] During the pathogenesis of NIDDM insulin-resistance can initiallybe counteracted by increasing insulin output by the pancreatic betacell. Ultimately, this compensation fails, beta cell function decreasesand overt diabetes results (McGarry (1992) Science 258: 766-770).Manipulating beta cell function is a second point where fatty acidtransporter blockers may be beneficial for diabetes. While no FATPhomolog has been identified so far that is expressed in the beta cell ofthe pancreas, the data described below suggest the existence of such atransporter and the sequence information included herein provides themeans to identify such a transporter by degenerate PCR, using primers toregions conserved in all FATP family members or by low stringencyhybridization. It has been demonstrated that exposure of pancreaticbeta-cells to FFAs increases the basal rate of insulin secretion; thisin turn leads to a decrease in the intracellular stores of insulin,resulting in decreased capacity for insulin secretion after chronicexposure (Bollheimer et al., (1998) J. Clin. Invest. 10 1:1094-1101).The effects of FFAs are again likely to be mediated by intracellularlong chain fatty acyl CoA molecules (Liu et al., (1998) J. Clin. Invest.101:1870-1875). FFAs have also been demonstrated to increase beta cellapoptosis (Shimabukuro et al., (1998) Proc. Nat. Acad. Sci. USA95:2498-2502), possibly contributing to the decrease in beta cellnumbers in late stage NIDDM.

[0147] Another finding with potentially broad implications is theidentification of a FATP homologue in M. tuberculosis. Tuberculosiscauses more deaths. worldwide than any other infectious agent anddrug-resistant tuberculosis is re-emerging as a problem inindustrialized nations (Bloom, B. R. & Small, P. M. (1998) N. Engl. J.Med. 338:677-678). Mycobacterium tuberculosis has about 250 enzymesinvolved in fatty acid metabolism, compared with only about 50 in E.coli. It has been suggested that, living as a pathogen, the mycobacteriaare largely lipolytic, rather than lipogenic, relying on the lipidswithin mammalian cells and the tubercle (Cole, S. T. et al., Nature393:537-544 (1998)). The de novo synthesis of fatty acids inMycobacterium leprae is insufficient to maintain growth (Wheeler, P. R.,Bulmer, K & Ratledge, C. (1990) J. Gene. Microbiol. 136:211-217). Thus,it is reasonable to expect that inhibitors of mtFATP will serve astherapeutics for tuberculosis. FATPs expressed in mycobacteria can betargeted to reduce or prevent replication of mycobacteria (e.g., toreduce or prevent replication of M. tuberculosis) and, thus, reduce orprevent their adverse effects. For example, a FATP or FATPs expressed byM. tuberculosis can be targeted and inhibited, thus reducing orpreventing growth of this pathogen (and tuberculosis in humans and othermammals). An inhibitor of an M. tuberculosis FATP can be identified,using methods described herein (e.g., expressing the FATP in anappropriate host cell, such as E. coli or COS cells; contacting thecells with an agent or drug to be assessed for its ability to inhibitthe FATP and, as a result, mycobacterial growth, and assessing itseffects on growth). A drug or agent identified in this manner can befurther tested for its ability to inhibit a M. tuberculosis FATP and M.tuberculosis infection in an appropriate animal model or in humans. Amethod of inhibiting mycobacterial growth, particularly growth of M.tuberculosis, and compounds useful as drugs for doing so are also thesubject of this invention.

[0148] An isolated polynucleotide encoding mtFATP, like otherpolynucleotides encoding FATPs of the FATP family, can be incorporatedinto vectors, nucleic acids of viruses, and other nucleic acidconstructs that can be used in various types of host cells to producemtFATP. This mtFATP can be used, as it appears on the surface of cells,or in various artificial membrane systems, to assess fatty acidtransport function, to identify ligands and molecules that aremodulators of fatty acid transport activity. Molecules found to beinhibitors of mtFATP function can be incorporated into pharmaceuticalcompositions to administer to a human for the treatment of tuberculosis.

[0149] Particular embodiments of the invention are polynucleotidesencoding a FATP of Cochliobolus (Helminthosporium) heterostrophus orportions or variants thereof, the isolated or recombinantly producedFATP, methods for assessing whether an agent binds to the chFATP, andfurther methods for assessing the effect of an agent being tested forits ability to modulate fatty acid transport activity. Cochliobolusheterostrophus is an ascomycete that is the cause of southern corn leafblight, an economically important threat to the corn crop in the UnitedStates. The related species C. sativus causes crown rot and common rootrot in wheat and barley. One or more FATPs of C. heterostrophus can betargeted for the identification of an inhibitor of chFATP function,which can be then be used as an agent effective against infection ofplants by C. heterostrophus and related organisms. Methods describedherein that were applied in studying the expression of a FATP gene andthe function of the FATP in its natural site of expression or in a hostcell, can be used in the study of the chFATP gene and protein.

[0150]Magnaporthe grisea (rice blast) is an economically importantfungal pathogen of rice. Further embodiments of the invention arenucleic acid molecules encoding a FATP of Magnaporthe grisea, portionsthereof, or variants thereof, isolated mgFATP, nucleic acid constructs,and engineered cells expressing mgFATP. Other aspects of the inventionare assays to identify an agent which binds to mgFATP and assays toidentify an agent which modulates the function of mgFATP in cells inwhich mgFATP is expressed or in artificial membrane systems. Agentsidentified as inhibiting mgFATP activity can be developed intoanti-fungal agents to be used to treat rice infected with rice blast.

[0151]Caenorhabditis elegans is a nematode related to plant pathogensand human parasites. An isolated polynucleotide which encodes ceFATP,like other polynucleotides encoding FATPs of the FATP family describedherein, can be incorporated into nucleic acid vectors and otherconstructs that can be used in various types of cells to produce ceFATP.ceFATP as it occurs in cells or as it can be isolated or incorporatedinto various artificial or reconstructed membrane systems, can be usedto assess fatty acid transport, and to identify ligands and agents thatmodulate fatty acid transport activity. Agents found by such assays tobe inhibitors of ceFATP activity can be incorporated into compositionsfor the treatment of diseases caused by genetically related organismswith a FATP of similar sensitivity to the agents.

[0152]Aspergillus nidulans is one of a family of fungal species that caninfect humans. Further embodiments of the invention of the family ofpolynucleotides encoding FATPs are polynucleotides encoding a FATP ofAspergillus nidulans, and vectors and host cells that can be constructedto comprise such polynucleotides. Further embodiments are a polypeptideencoded by such polynucleotides, portions thereof having one or morefunctions characteristic of a FATP, and various methods. The methodsinclude those for identifying agents that bind to a FATP and those forassessing the effect of an agent being tested for its ability tomodulate fatty acid transport activity. Those agents found to inhibitfatty acid transport function can be used in compositions as anti-fungalpharmaceuticals, or can be modified for greater effectiveness as apharmaceutical.

[0153] One aspect of the invention relates to isolated nucleic acidsthat encode a FATP as described herein, such as those FATPs having anamino acid sequence in FIG. 45 (SEQ ID NO:47), FIG. 47 (SEQ ID NO:49),FIG. 112 (SEQ ID NO: 117), FIG. 51 (SEQ ID NO:53), FIG. 53 (SEQ IDNO:55), and FIG. 55 (SEQ ID NO:57) and nucleic acids closely relatedthereto as described herein.

[0154] Using the information provided herein, such as a nucleic acidsequence set forth in FIGS. 44A-44C (SEQ ID NO:46), FIGS. 46A and 46B(SEQ ID NO:48), FIG. 112 (SEQ ID NO:116), FIGS. 50A-50C (SEQ ID NO:52),FIG. 52 (SEQ ID NO:54), and FIGS. 54A-54C (SEQ ID NO:56), a nucleic acidof the invention encoding a FATP polypeptide has been obtained usingstandard cloning and screening methods, such as those for cloning andsequencing cDNA library fragments, followed by obtaining a full lengthclone. For example, to obtain a nucleic acid of the invention, a libraryof clones of cDNA of human or other mammalian DNA can be probed with alabeled oligonucleotide, such as a radiolabeled oligonucleotide,preferably about 17 nucleotides or longer, derived from a partialsequence. Clones carrying DNA identical to that of the probe can then bedistinguished using stringent (also, “high stringency”) hybridizationconditions. By sequencing the individual clones thus identified withsequencing primers designed from the original sequence it is thenpossible to extend the sequence in both directions to determine the fulllength sequence. Suitable techniques are described, for example, inCurrent Protocols in Molecular Biology (F. M. Ausubel et al, eds),containing supplements through Supplement 42, 1998, John Wiley and Sons,Inc., especially chapters 5, 6 and 7.

[0155] Embodiments of the invention include isolated nucleic acidmolecules comprising any of the following nucleotide sequences: 1.) anucleotide sequence which encodes a protein comprising the amino acidsequence of hsFATP1 (SEQ ID NO:47), the amino acid sequence of hsFATP2(SEQ ID NO:49), the amino acid sequence of hsFATP3 (SEQ ID NO:117), theamino acid sequence of hsFATP4 (SEQ ID NO: 53), the amino acid sequenceof hsFATP5 (SEQ ID NO:55) or the amino acid sequence of hsFATP6 (SEQ IDNO:57); 2.) nucleotide sequences of hsFATP1, hsFATP2, hsFATP3, hsFATP4,hsFATP5, or hsFATP6 (SEQ ID NO:46, 48, 116, 52, 54, or 56,respectively); 3.) a nucleotide sequence which is complementary to thenucleotide sequence of hsFATP1 (SEQ ID NO:46), hsFATP2 (SEQ ID NO:48),hsFATP3 (SEQ ID NO:116), hsFATP4 (SEQ ID NO:52), hsFATP5 (SEQ ID NO:54)or hsFATP6 (SEQ ID NO:56); 4.) a nucleotide sequence which consists ofthe coding region of hsFATP1 (SEQ ID NO:46), the coding region ofhsFATP2 (SEQ ID NO:48), the coding region of hsFATP3 (SEQ ID NO:116),the coding region of hsFATP4 (SEQ ID NO:52), the coding region ofhsFATP5 (SEQ ID NO:54), or the coding region of hsFATP6 (SEQ ID NO:56).

[0156] The invention further relates to nucleic acids (nucleic acidmolecules or polynucleotides) having nucleotide sequences identical overtheir entire length to those shown in the figures, for instance FIGS.44A-44C (SEQ ID NO:46), FIGS. 46A and 46B (SEQ ID NO:48), FIGS. 111A-B(SEQ ID NO:116), FIGS. 50A-50C (SEQ ID NO:52), FIG. 52 (SEQ ID NO:54),and FIGS. 54A-54C (SEQ ID NO:56). It further relates to DNA, which dueto the degeneracy of the genetic code, encodes a FATP encoded by one ofthe FATP-encoding DNAs, whose amino acid sequence is provided herein.Also provided by the invention are nucleic acids having the codingsequences for the mature polypeptides or fragments in reading frame withother coding sequences, such as those encoding a leader or secretorysequence, a pre-, or pro- or prepro-protein sequence. The nucleic acidsof the invention encompass nucleic acids that include a singlecontinuous region or discontinuous regions encoding the polypeptide,together with additional regions, that may also contain coding ornon-coding sequences. The nucleic acids may also contain non-codingsequences, including, for example, but not limited to, non-coding 5′ and3′ sequences, such as the transcribed, non-translated sequences,termination signals, ribosome binding sites, sequences that stabilizemRNA, introns, polyadenylation signals, and additional coding sequenceswhich encode additional amino acids. For example, a marker sequence thatfacilitates purification of the fused polypeptide can be encoded. Incertain embodiments of the invention, the marker sequence can be ahexa-histidine peptide, as provided in the pQE vector (Qiagen, Inc.,Venlo, The Netherlands) and described in Gentz et al., Proc. Natl. Acad.Sci. USA 86: 821-824 (1989), or an HA tag (Wilson et al., Cell 37: 767(1984)), or a sequence encoding glutathione S-transferase of Schistosomajaponicum (vectors available from Pharmacia; see Smith, D. B. andJohnson K. S., Gene 67:31 (1988) and Kaelin, W. G. et al., Cell 70:351(1992)). Nucleic acids of the invention also include, but are notlimited to, nucleic acids comprising a structural gene and its naturallyassociated sequences that control gene expression.

[0157] The invention further relates to nucleic acids (nucleic acidmolecules or polynucleotides) that encode a FATP polypeptide. In aparticular embodiment, a nucleic acid encodes a portion of a FATP whichincludes a motif or domain, for example, a lipocalin domain or anAMP-binding domain. Such a polypeptide portion can be a functionalportion of a FATP protein. The term “lipocalin domain” is an artrecognized term and as used herein refers to a particular domain presentin FATP proteins. This domain is described as including regions ofsequence homology as well as a common tertiary structure represented asan eight stranded antiparallel beta-barrel. (see Banaszak, L. et al.,Advances in Protein Chemistry, 45: 89-151). Many lipocalin domains canbe identified structurally as a sequence contained within the generalformula:[DENG]-X-[DENQGSTARK]-X(0,2)-[DENQARK]-[LIVFY]-{CP}-G-{C}-W-[FYWLRH-X]-[LIVMTA],e.g., the lipocalin signature sequence or consensus pattern (SEQ ID NO:125). One skilled in the art will recognize that a lipocalin domain fora particular FATP protein can vary in sequence from this generalformula. A FATP lipocalin domain can be, for example, identical to thelipocalin signature sequence or can exhibit 60, 65, 70, 75, 80, 85, 90,95 or greater per cent sequence identity compared to the general formulaprovided that it retains lipocalin binding function. For example, alipocalin domain for each of the human FATPs, hsFATP 1 (SEQ ID NO:126),hsFATP2 (SEQ ID NO:127), hsFATP3 (SEQ ID NO:128), hsFATP4 (SEQ IDNO:129), hsFATP5 (SEQ ID NO: 130), and hsFATP6 (SEQ ID NO:131) has beenidentified. The pattern of these lipocalin domains are highly conservedacross the FATP family.

[0158] A nucleic acid encoding a portion of a FATP polypeptide canencode one or more domains, and also can include additional nucleotides.For example, the nucleic acid can also include nucleotide sequences thatencode a portion of a FATP protein that is upstream from a lipocalindomain. As the term “upstream” or “upstream sequences” is used herein inrelation to the lipocalin domain, it is intended to refer to thenucleotide sequence which encodes all or a portion of a FATP proteinlocated between the signal peptide (when one is present) and thelipocalin domain. In the absence of a signal peptide, the term refers tothe nucleotide sequence which encodes all or a portion of a FATP proteinbetween the lipocalin domain and the amino terminus (see FIG. 115).

[0159] The invention further relates to variants, includingnaturally-occurring allelic variants, of those nucleic acids describedspecifically herein by DNA sequence, that encode variants of suchpolypeptides as those having the amino acid sequences shown in FIG. 45(SEQ ID NO:47), FIG. 47 (SEQ ID NO:49), FIG. 112 (SEQ ID NO: 117), FIG.51 (SEQ ID NO:53) FIG. 53 (SEQ ID NO:55), or FIG. 55 (SEQ ID NO:57).Such variants include nucleic acids encoding variants of theabove-listed amino acid sequences, wherein those variants have several,such as 5 to 10, 1 to 5, or 3, 2 or 1 amino acids substituted, deleted,or added, in any combination. Variants include polynucleotides encodingpolypeptides with at least 95% but less than 100% amino acid sequenceidentity to the polypeptides described herein by amino acid sequence.Variant polynucleotides hybridize, under low to high stringencyconditions, to the alleles described herein by DNA sequence. In oneembodiment, variants have silent substitutions, additions and deletionsthat do not alter the properties and activities of the FATP. Allelicvariants of the polynucleotides encoding hsFATP1 (FIG. 45; SEQ IDNO:47), hsFATP2 (FIG. 47; SEQ ID NO:49), hsFATP3 (FIG. 112; SEQ IDNO:117), hsFATP4 (FIG. 51; SEQ ID NO:53), hsFATP5 (FIG. 53; SEQ IDNO:55) and hsFATP6 (FIG. 55; SEQ ID NO:57) will be identified as mappingto chromosomal locations listed for the corresponding wild type genes inTable 2 in Example 1.

[0160] Orthologous genes are gene loci in different species that aresufficiently similar to each other in their nucleotide sequences tosuggest that they originated from a common ancestral gene. Orthologousgenes arise when a lineage splits into two species, rather than when agene is duplicated within a genome. Proteins that are orthologs areencoded by genes of two different species, wherein the genes are said tobe orthologous.

[0161] The invention further relates to polynucleotides encodingpolypeptides which are orthologous to those polypeptides having aspecific amino acid sequence described herein, such as the amino acidsequences shown in FIG. 45 (SEQ ID NO:47), FIG. 47 (SEQ ID NO:49), FIG.112 (SEQ ID NO: 117), FIG. 51 (SEQ ID NO:53), FIG. 53 (SEQ ID NO:55), orFIG. 55 (SEQ ID NO:57). These polynucleotides, which can be calledortholog polynucleotides, encode orthologous polypeptides that can rangein amino acid sequence identity to a reference amino acid sequencedescribed herein, from about 65% to less than 100%, but preferably 70%to 80%, more preferably 80% to 90%, and still more preferably 90% toless than 100%. Orthologous polypeptides can also be those polypeptidesthat range in amino acid sequence similarity to a reference amino acidsequence described herein from about 75% to 100%, within the signaturesequence. The amino acid sequence similarity between the signaturesequences of orthologous polypeptides is preferably 80%, more preferably90%, and still more preferably, 95%. The ortholog polynucleotides encodepolypeptides that have similar functional characteristics (e.g., fattyacid transport activity) and similar tissue distribution, as appropriateto the organism from which the ortholog polynucleotides can be isolated.

[0162] Ortholog polynucleotides can be isolated from (e.g., by cloningor nucleic acid amplification methods) a great number of species, asshown by the sample of FATPs from evolutionarily divergent speciesdescribed herein (see, e.g., FIGS. 44A-C through FIG. 89). Orthologpolynucleotides corresponding to those in FIG. 45 (SEQ ID NO:47), FIG.47 (SEQ ID NO:49), FIGS. 111A-B (SEQ ID NO:116), FIG. 51 (SEQ ID NO:53),FIG. 52 (SEQ ID NO:55) and FIG. 55 (SEQ ID NO:57) are those which can beisolated from mammals such as rat, dog, chimpanzee, monkey, baboon, pig,rabbit and guinea pig, for example.

[0163] Further variants that are fragments of the nucleic acids of theinvention may be used to synthesize full-length nucleic acids of theinvention, such as by use as primers in a polymerase chain reaction. Asused herein, the term primer refers to a single-stranded oligonucleotidewhich acts as a point of initiation of template-directed DNA synthesisunder appropriate conditions (e.g., in the presence of four differentnucleoside triphosphates and an agent for polymerization, such as DNA orRNA polymerase or reverse transcriptase) in an appropriate buffer and ata suitable temperature. The appropriate length of a primer depends onthe intended use of the primer, but typically ranges from 15 to 30nucleotides. Short primer molecules generally require coolertemperatures to form sufficiently stable hybrid complexes with thetemplate. A primer need not reflect the exact sequence of the template,but must be sufficiently complementary to hybridize with a template. Theterm primer site refers to the area of the target DNA to which a primerhybridizes. The term primer pair refers to a set of primers including a5′ (upstream) primer that hybridizes with the 5′ end of the DNA sequenceto be amplified and a 3′ (downstream) primer that hybridizes with thecomplement of the 3′ end of the sequence to be amplified.

[0164] Further embodiments of the invention are nucleic acids that areat least 80% identical over their entire length to a nucleic aciddescribed herein, for example a nucleic acid having the nucleotidesequence in FIGS. 44A-44C (SEQ ID NO:46), FIGS. 46A-46B (SEQ ID NO:48),FIGS. 111A-B (SEQ ID NO:116), FIGS. 50A-50C (SEQ ID NO:52), FIG. 52 (SEQID NO:54), and FIGS. 54A-54C (SEQ ID NO:56). Additional embodiments arenucleic acids, and the complements of such nucleic acids, having atleast 90% nucleotide sequence identity to the above-described sequences,and nucleic acids having at least 95% nucleotide sequence identity. Inpreferred embodiments, DNA of the present invention has 97% nucleotidesequence identity, 98% nucleotide sequence identity, or at least 99%nucleotide sequence identity with the DNA whose sequences are presentedherein.

[0165] Other embodiments of the invention are nucleic acids that are atleast 80% identical in nucleotide sequence to a nucleic acid encoding apolypeptide having an amino acid sequence as set forth in FIG. 45 (SEQID NO:47), FIG. 47 (SEQ ID NO:49), FIG. 112 (SEQ ID NO:1 17), FIG. 51(SEQ ID NO:53), FIG. 53 (SEQ ID NO:55) or FIG. 55 (SEQ ID NO:57), or assuch amino acid sequences are set forth elsewhere herein, and nucleicacids that are complementary to such nucleic acids. Specific embodimentsare nucleic acids having at least 90% nucleotide sequence identity to anucleic acid encoding a polypeptide having an amino acid sequence asdescribed in the list above, nucleic acids having at least 95% sequenceidentity, and nucleic acids having at least 97% sequence identity.

[0166] The terms “complementary” or “complementarity” as used herein,refer to the natural binding of polynucleotides under permissive saltand temperature conditions by base-pairing. Complementarity between twosingle-stranded molecules may be “partial” in which only some of thenucleic acids bind, or it may be complete when total complementarityexists between the single-stranded molecules (that is, when A-T and G-Cbase pairing is 100% complete). The degree of complementarity betweennucleic acid strands has significant effects on the efficiency andstrength of hybridization between nucleic acid strands. This is ofparticular importance in amplification reactions, which depend onbinding between nucleic acid strands.

[0167] The invention further includes nucleic acids that hybridize tothe above-described nucleic acids, especially those nucleic acids thathybridize under stringent hybridization conditions. “Stringenthybridization conditions” or “high stringency conditions” generallyoccur within a range from about T_(m) minus 5° C. (5° C. below thestrand dissociation temperature or melting temperature (T_(m)) of theprobe nucleic acid molecule) to about 20° C. to 25° C. below T_(m). Aswill be understood by those of skill in the art, the stringency ofhybridization may be altered in order to identify or detect moleculeshaving identical or related polynucleotide sequences. An example of highstringency hybridization follows. Hybridization solution is (6× SSC/10mM EDTA/0.5% SDS/5× Denhardt's solution/100 μg/ml sheared and denaturedsalmon sperm DNA). Hybridization is at 64-65° C. for 16 hours. Thehybridized blot is washed two times with 2× SSC/0.5% SDS solution atroom temperature for 15 minutes each, and two times with 0.2× SSC/0.5%SDS at 65° C., for one hour each. Further examples of high stringencyconditions can be found on pages 2.10.1-2.10.16 (see particularly2.10.8-11) and pages 6.3.1-6 in Current Protocols in Molecular Biology(Ausubel, F. M. et al., eds., containing supplements up throughSupplement 42, 1998). Examples of high, medium, and low stringencyconditions can be found on pages 36 and 37 of WO 98/40404, which areincorporated herein by reference.

[0168] The invention further relates to nucleic acids obtainable byscreening an appropriate library with a probe having a nucleotidesequence such as that set forth in FIGS. 44A-44C (SEQ ID NO:46), FIGS.46A-46B (SEQ ID NO:48), FIG. 111 (SEQ ID NO:116), FIGS. 50A-50C (SEQ IDNO:52), FIG. 52 (SEQ ID NO:54) or FIGS. 54A-54C (SEQ ID NO:56), or aprobe which is a sufficiently long fragment of any of the above; andisolating the nucleic acid. Such probes generally can comprise at least15 nucleotides. Nucleic acids obtainable by such screenings may includeRNAs, cDNAs and genomic DNA, for example, encoding FATPs of the FATPfamily described herein.

[0169] Further uses for the nucleic acid molecules of the invention,whether encoding a full-length FATP or whether comprising a contiguousportion of a nucleic acid molecule such as one given in SEQ ID NO:46,48, 116, 52, 54, or 56, include use as markers for tissues in which thecorresponding protein is preferentially expressed (to identifyconstitutively expressed proteins or proteins produced at a particularstage of tissue differentiation or stage of development of a diseasestate); as molecular weight markers on southern gels; as chromosomemarkers or tags (when labeled, for example with biotin, a radioactivelabel or a fluorescent label) to identify chromosomes or to map relatedgene positions; to compare with endogenous DNA sequences in a mammal toidentify potential genetic disorders; as probes to hybridize and thusidentify, related DNA sequences; as a source of information to derivePCR primers for genetic fingerprinting; as a probe to “subtract-out”known sequences in the process of discovering other novel nucleic acidmolecules; for selecting and making oligomers for attachment to a “genechip” or other support, to be used, for example, for examination ofexpression patterns; to raise anti-protein antibodies using DNAimmunization techniques; and as an antigen to raise anti-DNA antibodiesor to elicit another immune response.

[0170] In certain embodiments, a contiguous portion can be about 15, 25,30, 40, 50, 75, 100, 200, 300, 400, 500, 750, 1000, 1100, 1250, 1500 ormore nucleotides in length. In a particular embodiment, the contiguousportion encompasses the signature sequence of a FATP and is about 1080nucleotides in length.

[0171] Further methods to obtain nucleic acids encoding FATPs of theFATP family include PCR and variations thereof (e.g., “RACE” PCR andsemi-specific PCR methods). Portions of the nucleic acids having anucleotide sequence set forth in FIGS. 44A-44C (SEQ ID NO:46), FIGS.46A-46B (SEQ ID NO:48), FIGS. 111A-B (SEQ ID NO:116), FIGS. 50A-50C (SEQID NO:52), FIG. 52 (SEQ ID NO:54) or FIGS. 54A-54C (SEQ ID NO:56),(especially “flanking sequences” on either side of a coding region) canbe used as primers in methods using the polymerase chain reaction, toproduce DNA from an appropriate template nucleic acid.

[0172] Once a fragment of the FATP gene is generated by PCR, it can besequenced, and the sequence of the product can be compared to other DNAsequences, for example, by using the BLAST Network Service at theNational Center for Biotechnology Information. The boundaries of theopen reading frame can then be identified using semi-specific PCR orother suitable methods such as library screening. Once the 5′ initiatormethionine codon and the 3′ stop codon have been identified, a PCRproduct encoding the full-length gene can be generated using genomic DNAas a template, with primers complementary to the extreme 5′ and 3′ endsof the gene or to their flanking sequences. The full-length genes canthen be cloned into expression vectors for the production of functionalproteins.

[0173] The invention also relates to isolated proteins or polypeptidessuch as those encoded by nucleic acids of the present invention.Isolated proteins can be purified from a natural source or can be maderecombinantly. Proteins or polypeptides referred to herein as “isolated”are proteins or polypeptides that exist in a state different from thestate in which they exist in cells in which they are normally expressedin an organism, and include proteins or polypeptides obtained by methodsdescribed herein, similar methods or other suitable methods, and alsoinclude essentially pure proteins or polypeptides, proteins orpolypeptides produced by chemical synthesis or by combinations ofbiological and chemical methods, and recombinant proteins orpolypeptides which are isolated. Thus, the term “isolated” as usedherein, indicates that the polypeptide in question exists in a physicalmilieu distinct from that in which it occurs in nature. Thus, “isolated”includes existing in membrane fragments and vesicles membrane fractions,liposomes, lipid bilayers and other artificial membrane systems. Anisolated FATP may be substantially isolated with respect to the complexcellular milieu in which it naturally occurs, and may even be purifiedessentially to homogeneity, for example as determined by PAGE or columnchromatography (for example, HPLC), but may also have further cofactorsor molecular stabilizers, such as detergents, added to the purifiedprotein to enhance activity. In one embodiment, proteins or polypeptidesare isolated to a state at least about 75% pure; more preferably atleast about 85% pure, and still more preferably at least about 95% pure,as determined by Coomassie blue staining of proteins onSDS-polyacrylamide gels. Proteins or polypeptides referred to herein as“recombinant” are proteins or polypeptides produced by the expression ofrecombinant nucleic acids.

[0174] In a preferred embodiment, an isolated polypeptide comprising aFATP, a functional portion thereof, or a functional equivalent of theFATP, has at least one function characteristic of a FATP, for example,transport activity, binding function (e.g., a domain which binds toAMP), or antigenic function (e.g., binding of antibodies that also bindto a naturally-occurring FATP, as that function is found in an antigenicdeterminant). Functional equivalents can have activities that arequantitatively similar to, greater than, or less than, the referenceprotein. These proteins include, for example, naturally occurring FATPsthat can be purified from tissues in which they are produced (includingpolymorphic or allelic variants), variants (e.g., mutants) of thoseproteins and/or portions thereof. Such variants include mutantsdiffering by the addition, deletion or substitution of one or more aminoacid residues, or modified polypeptides in which one or more residuesare modified, and mutants comprising one or more modified residues.Portions or fragments of a FATP can range in size from four amino acidresidues to the entire amino acid sequence minus one amino acid andinclude contiguous portions or fragments about 4, 5, 6, 7, 8, 9, 10, 15,25, 30, 40, 50, 75, 100, 150, 200, 300, 400, 500, 600 or more amino acidresidues in length. In one particular embodiment, the portion orfragment includes the signature sequence of a FATP polypeptide and isabout 360 amino acid residues in length.

[0175] The isolated proteins of the invention preferably includemammalian fatty acid transport proteins of the FATP family of homologousproteins. In one embodiment, the extent of amino acid sequencesimilarity between a polypeptide having one of the amino acid sequencesshown in FIG. 45 (SEQ ID NO:47), FIG. 47 (SEQ ID NO:49), FIG. 112 (SEQID NO:117), FIG. 51 (SEQ ID NO:53), FIG. 53 (SEQ ID NO:55), or FIG. 55(SEQ ID NO:57), and the respective functional equivalents of thesepolypeptides is at least about 88%. In other embodiments, the degree ofamino acid sequence similarity between a FATP and its respectivefunctional equivalent is at least about 91%, at least about 94%, or atleast about 97%.

[0176] The polypeptides of the invention also include those FATPsencoded by polynucleotides which are orthologous to thosepolynucleotides, the sequences of which are described herein in whole orin part. FATPs which are orthologs to those described herein by aminoacid sequence, in whole or in part, are, for example, fatty acidtransport proteins 1-6 of dog, rat, chimpanzee, monkey, rabbit, guineapig, baboon and pig, and are also embodiments of the invention.

[0177] To determine the percent identity or similarity of two amino acidsequences or of two nucleic acid sequences, the sequences are alignedfor optimal comparison purposes (e.g., gaps can be introduced in one orboth of a first and a second amino acid or nucleic acid sequence foroptimal alignment, and non-homologous (dissimilar) sequences can bedisregarded for comparison purposes). In a preferred embodiment, thelength of a reference sequence aligned for comparison purposes is atleast 30%, preferably at least 40%, more preferably at least 50%, evenmore preferably at least 60%, and even more preferably at least 70%,80%, or 90% of the length of the reference sequence. The amino acidresidues or nucleotides at corresponding amino acid positions ornucleotide positions are then compared. When a position in the firstsequence is occupied by the same amino acid residue or nucleotide as thecorresponding position in the second sequence, then the molecules areidentical at that position (as used herein, amino acid or nucleic acid“identity” is equivalent to amino acid or nucleic acid “similarity”).The percent identity between the two sequences is a function of thenumber of identical positions shared by the sequences, taking intoaccount the number of gaps, and the length of each gap, which need to beintroduced for optimal alignment of the two sequences.

[0178] The invention also encompasses polypeptides having a lower degreeof identity but having sufficient similarity so as to perform one ormore of the same functions performed by the polypeptides describedherein by amino acid sequence. Similarity for a polypeptide isdetermined by conserved amino acid substitution. Such substitutions arethose that substitute a given amino acid in a polypeptide by anotheramino acid of like characteristics. Conservative substitutions arelikely to be phenotypically silent. Typically seen as conservativesubstitutions are the replacements, one for another, among the aliphaticamino acids Ala, Val, Leu, and Ile; interchange of the hydroxyl residuesSer and Thr, exchange of the acidic residues Asp and Glu, substitutionbetween the amide residues Asn and Gln, exchange of the basic residuesLys and Arg and replacements among the aromatic residues Phe and Tyr.Guidance concerning which amino acid changes are likely to bephenotypically silent is found in Bowie et al., Science 247:1306-1310(1990). TABLE 1 Conservative Amino Acid Substitutions AromaticPhenylalanine Tryptophan Tyrosine Hydrophobic Leucine Isoleucine ValinePolar Glutamine Asparagine Basic Arginine Lysine Histidine AcidicAspartic Acid Glutamic Acid Small Alanine Serine Threonine MethionineGlycine

[0179] The comparison of sequences and determination of percent identityand similarity between two sequences can be accomplished using amathematical algorithm. (Computational Molecular Biology, Lesk, A. M.,ed., Oxford University Press, New York, 1988; Biocomputing: Informaticsand Genome Projects, Smith, D. W., ed., Academic Press, New York, 1993;Computer Analysis of Sequence Data, Part 1, Griffin, A. M., and Griffin,H. G., eds., Humana Press, New Jersey, 1994; Sequence Analysis inMolecular Biology, von Heinje, G., Academic Press, 1987; and SequenceAnalysis Primer, Gribskov, M. and Devereaux, J., eds., M. StocktonPress, New York, 1991). In a preferred embodiment, the percent identitybetween two amino acid sequences is determined using the Needleman andWunsch (J. Mol. Biol. (48):444-453 (1970)) algorithm which has beenincorporated into the GAP program in the GCG software package (availableon the worldwide web at gcg.com), using either a Blossom 62 matrix or aPAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and alength weight of 1, 2, 3, 4, 5, or 6. In yet another preferredembodiment, the percent identity between two nucleotide sequences isdetermined using the GAP program in the GCG software package (Devereux,J., et al., Nucleic Acids Res. 12(1):387 (1984)), (available on theworldwide web at gcg.com), using a NWSgapdna.CMP matrix and a gap weightof 40, 50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6. Inanother embodiment, the percent identity between two amino acid ornucleotide sequences is determined using the algorithm of E. Meyers andW. Miller (CABIOS, 4:11-17 (1989)) which has been incorporated into theALIGN program (version 2.0), using a PAM120 weight residue table, a gaplength penalty of 12 and a gap penalty of 4.

[0180] The nucleic acid and protein sequences of the present inventioncan further be used as a “query sequence” to perform a search againstdatabases to, for example, identify other family members or relatedsequences. Such searches can be performed using the NBLAST and XBLASTprograms (version 2.0) of Altschul, et al. (J. Mol. Biol. 215:403-10(1990)). BLAST nucleotide searches can be performed with the NBLASTprogram, score=100, word length=12 to obtain nucleotide sequenceshomologous to (with calculatably significant similarity to) the nucleicacid molecules of the invention. BLAST protein searches can be performedwith the XBLAST program, score=50, word length=3 to obtain amino acidsequences homologous to the proteins of the invention. To obtain gappedalignments for comparison purposes, Gapped BLAST can be utilized asdescribed in Altschul et al., (Nucleic Acids Res. 25(17):3389-3402(1997)). When utilizing BLAST and gapped BLAST programs, the defaultparameters of the respective programs (e.g., XBLAST and NBLAST) can beused. (see the worldwide web at ncbi.nlm.nih.gov)

[0181] Similarity for nucleotide and amino acid sequences can be definedin terms of the parameters set by the Advanced Blast search availablefrom NCBI (the National Center for Biotechnology Information (see, forAdvanced BLAST the worldwide web atncbi.nlm.nih.gov/cgi-bin/BLAST/nph-newblast?Jform=1). These defaultparameters, recommended for a query molecule of length greater than 85amino acid residues or nucleotides have been set as follows: gapexistence cost, 11, per residue gap cost, 1; lambda ratio, 0.85. Furtherexplanation of version 2.0 of BLAST can be found on related websitepages and in Altschul, S. F. et al, Nucleic Acids Res. 25:3389-3402(1997).

[0182] In certain embodiments, a contiguous portion can be about 4, 5,6, 7, 8, 9, 10, 15, 25, 30, 40, 50, 75, 100, 150, 200, 300, 400, 500,600 or more amino acid residues in length. In one particular embodiment,the portion or fragment includes the signature sequence of a FATPpolypeptide and is about 360 amino acid residues in length.

[0183] The invention further relates to fusion proteins, comprising aFATP or functional portion thereof (as described above) as a firstmoiety, linked to a second moiety not occurring in the FATP as found innature. Thus, the second moiety can be an amino acid, peptide orpolypeptide. The first moiety can be in an N-terminal location,C-terminal location or internal to the fusion protein. In oneembodiment, the fusion protein comprises a FATP as the first moiety, anda second moiety comprising a linker sequence and an affinity ligand.Fusion proteins can be produced by a variety of methods. For example, afusion protein can be produced by the insertion of a FATP gene orportion thereof into a suitable expression vector, such as Bluescript SK+/− (Stratagene, La Jolla, Calif.), pGEX-4T-2 (Pharmacia, Peapack,N.J.), pET-24(+) (Novagen, Madison, Wis.), or vectors of similarconstruction. The resulting construct can be introduced into a suitablehost cell for expression. Upon expression, fusion protein can bepurified from cells by means of a suitable affinity matrix (See e.g.,Current Protocols in Molecular Biology, Ausubel, F. M. et al., eds.,Vol. 2, pp. 16.4.1-16.7.8, containing supplements up through Supplement42, 1998).

[0184] The invention also relates to enzymatically produced,synthetically produced, or recombinantly produced portions of a fattyacid transport protein. Portions of a FATP can be made which have fullor partial function on their own, or which when mixed together (thoughfully, partially, or nonfunctional alone), spontaneously assemble withone or more other polypeptides to reconstitute a functional proteinhaving at least one function characteristic of a FATP.

[0185] Fragments of a FATP can be produced by direct peptide synthesis,for example those using solid-phase techniques (Roberge, J. Y. et al.,Science 269:202-204 (1995); Merrifield, J., J. Am. Chem. Soc.85:2149-2154 (1963)). Protein synthesis can be performed using manualtechniques or by automation. Automated synthesis can be carried outusing, for instance, an Applied Biosystems 431A Peptide Synthesizer(Perkin Elmer). Various fragments of a FATP can be synthesizedseparately and combined using chemical methods.

[0186] One aspect of the invention is a peptide or polypeptide havingthe amino acid sequence of a portion of a fatty acid transport proteinwhich is hydrophilic rather than hydrophobic, and ordinarily can bedetected as facing the outside of the cell membrane. Such a peptide orpolypeptide can be thought of as being an extracellular domain of theFATP, or a mimetic of said extracellular domain. It is known, forexample, that a portion of human FATP4 that includes a highly conservedmotif is involved in AMP-CoA binding function (Stuhlsatz-Krouper, S. M.et al., J. Biol. Chem. 44:28642-28650 (1998)).

[0187] The term “mimetic” as used herein, refers to a molecule, thestructure of which is developed from knowledge of the structure of theFATP of interest, or one or more portions thereof, and, as such, is ableto effect some or all of the functions of a FATP.

[0188] Portions of a FATP can be prepared by enzymatic cleavage of theisolated protein, or can be made by chemical synthesis methods. Portionsof a FATP can also be made by recombinant DNA methods in whichrestriction fragments, or fragments that may have undergone furtherenzymatic processing, or synthetically made DNAs are joined together toconstruct an altered FATP gene. The gene can be made such that itencodes one or more desired portions of a FATP. These portions of FATPcan be entirely homologous to a known FATP, or can be altered in aminoacid sequence relative to naturally occurring FATPs to enhance orintroduce desired properties such as solubility, stability, or affinityto a ligand. A further feature of the gene can be a sequence encoding anN-terminal signal peptide directed to the plasma membrane.

[0189] An extracellular domain can be determined by a hydrophobicityplot, such as those shown in FIGS. 28A, 29A, and 35A, or by ahydrophilicity plot such as those shown in FIGS. 28C, 29C, 35C, 91, 92and 93. A polypeptide or peptide comprising all or a portion of a FATPextracellular domain can be used in a pharmaceutical composition. Whenadministered to a mammal by an appropriate route, the polypeptide orpeptide can bind to fatty acids and compete with the native FATPs in themembrane of cells, thereby making fewer fatty acid molecules availableas substrates for transport into cells, and reducing the amount of fattyacids taken up by, for example, the heart, in the case of FATP6.

[0190] Another aspect of the invention relates to a method of producinga fatty acid transport protein, variants or portions thereof, and toexpression systems and host cells containing a vector appropriate forexpression of a fatty acid transport protein.

[0191] Cells that express a FATP, a variant or a portion thereof, or anortholog of a FATP described herein by amino acid sequence, can be madeand maintained in culture, under conditions suitable for expression, toproduce protein in the cells for cell-based assays, or to produceprotein for isolation. These cells can be procaryotic or eucaryotic.Examples of procaryotic cells that can be used for expression includeEscherichia coli, Bacillus subtilis and other bacteria. Examples ofeucaryotic cells that can be used for expression include yeasts such asSaccharomyces cerevisiae, Schizosaccharomyces pombe, Pichia pastoris andother lower eucaryotic cells, and cells of higher eucaryotes such asthose from insects and mammals, such as primary cells and cell linessuch as CHO, HeLa, 3T3 and BHK cells, preferably COS cells and humankidney 293 cells, and more preferably Jurkat cells. (See, e.g., Ausubel,F. M. et al., eds. Current Protocols in Molecular Biology, GreenePublishing Associates and John Wiley & Sons, Inc., containingSupplements up through Supplement 42, 1998)).

[0192] In one embodiment, host cells that produce a recombinant FATP, ora portion thereof, a variant, or an ortholog of a FATP described hereinby amino acid sequence, can be made as follows. A gene encoding a FATP,variant or a portion thereof can be inserted into a nucleic acid vector,e.g., a DNA vector, such as a plasmid, phage, cosmid, phagemid, virus,virus-derived vector (e.g., SV40, vaccinia, adenovirus, fowl pox virus,pseudorabies viruses, retroviruses) or other suitable replicon, whichcan be present in a single copy or multiple copies, or the gene can beintegrated in a host cell chromosome. A suitable replicon or integratedgene can contain all or part of the coding sequence for a FATP orvariant, operably linked to one or more expression control regionswhereby the coding sequence is under the control of transcriptionsignals and linked to appropriate translation signals to permittranslation. The vector can be introduced into cells by a methodappropriate to the type of host cells (e.g., transfection,electroporation, infection). For expression from the FATP gene, the hostcells can be maintained under appropriate conditions (e.g., in thepresence of inducer, normal growth conditions, etc.). Proteins orpolypeptides thus produced can be recovered (e.g., from the cells, as ina membrane fraction, from the periplasmic space of bacteria, fromculture medium) using suitable techniques. Appropriate membranetargeting signals may be incorporated into the expressed polypeptide.These signals may be endogenous to the polypeptide or they may beheterologous signals.

[0193] Polypeptides of the invention can be recovered and purified fromcell cultures (or from their primary cell source) by well-known methodsincluding ammonium sulfate or ethanol precipitation, acid extraction,anion or cation exchange chromatography, phosphocellulosechromatography, hydrophobic interaction chromatography, affinitychromatography, hydroxylapatite chromatography and high performanceliquid chromatography. Known methods for refolding protein can be usedto regenerate active conformation if the polypeptide is denatured duringisolation or purification.

[0194] In a further aspect of the invention are methods for assessingthe transport function of any of the fatty acid transport proteins orpolypeptides described herein, including orthologs, and in variations ofthese, methods for identifying an inhibitor (or an enhancer) of suchfunction and methods for assessing the transport function in thepresence of a candidate inhibitor or a known inhibitor.

[0195] A variety of systems comprising living cells can be used forthese methods. Cells to be used in fatty acid transport assays, andfurther in methods for identifying an inhibitor or enhancer of thisfunction, express one or more FATPs. See Examples 3, 6, 9, 12 and 14 fordata on tissue distribution of expression of FATPs, and Examples 10 and11 describing recombinant cells expressing FATP. Cells for use incell-based assays described herein can be drawn from a variety ofsources, such as isolated primary cells of various organs and tissueswherein one or more FATPs are naturally expressed. In some cases, thecells can be from adult organs, and in some cases, from embryonic orfetal organs, such as heart, lung, liver, intestine, skeletal muscle,kidney and the like. Cells for this purpose can also include cellscultured as fragments of organs or in conditions simulating the celltype and/or tissue organization of organs, in which artificial materialsmay be used as substrates for cell growth. Other types of cells suitablefor this purpose include cells of a cell strain or cell line (ordinarilycomprising cells considered to be “transformed”) transfected to expressone or more FATPs.

[0196] A further embodiment of the invention is a method for detecting,in a sample of cells, a fatty acid transport protein, a portion orfragment thereof, a fusion protein comprising a FATP or a portionthereof, or an ortholog as described herein, wherein the cells can be,for instance, cells of a tissue, primary culture cells, or cells of acell line, including cells into which nucleic acid has been introduced.The method comprises adding to the sample an agent that specificallybinds to the protein, and detecting the agent specifically bound to theprotein. Appropriate washing steps can be added to reduce nonspecificbinding to the agent. The agent can be, for example, an antibody, aligand or a substrate mimic. The agent can have incorporated into it, orhave bound to it, covalently or by high affinity non-covalentinteractions, for instance, a label that facilitates detection of theagent to which it is bound, wherein the label can be, but is not limitedto, a phosphorescent label, a fluorescent label, a biotin or avidinlabel, or a radioactive label. The means of detection of a fatty acidtransport protein can vary, as appropriate to the agent and label used.For example, for an antibody that binds to the fatty acid transportprotein, the means of detection may call for binding a second antibody,which has been conjugated to an enzyme, to the antibody which binds thefatty acid transport protein, and detecting the presence of the secondantibody by means of the enzymatic activity of the conjugated enzyme.

[0197] Similar principles can also be applied to a cell lysate or a morepurified preparation of proteins from cells that may comprise a fattyacid transport protein of interest, for example in the methods ofimmunoprecipitation, immunoblotting, immunoaffinity methods, that inaddition to detection of the particular FATP, can also be used inpurification steps, and qualitative and quantitative immunoassays. See,for instance, chapters 11 through 14 in Antibodies: A Laboratory Manual,E. Harlow and D. Lane, eds., Cold Spring Harbor Laboratory, 1988.

[0198] Isolated fatty acid transport protein or, an antigenicallysimilar portion thereof, especially a portion that is soluble, can beused in a method to select and identify molecules which bindspecifically to the FATP. Fusion proteins comprising all of, or aportion of, the fatty acid transport protein linked to a second moietynot occurring in the FATP as found in nature, can be prepared for use inanother embodiment of the method. Suitable fusion proteins for thispurpose include those in which the second moiety comprises an affinityligand (e.g., an enzyme, antigen, epitope). FATP fusion proteins can beproduced by the insertion of a gene encoding the FATP or a variantthereof, or a suitable portion of such gene into a suitable expressionvector, which encodes an affinity ligand (e.g., pGEX-4T-2 and pET-15b,encoding glutathione S-transferase and His-Tag affinity ligands,respectively). The expression vector can be introduced into a suitablehost cell for expression. Host cells are lysed and the lysate,containing fusion protein, can be bound to a suitable affinity matrix bycontacting the lysate with an affinity matrix.

[0199] In a particular embodiment, a nucleic acid encodes a portion of aFATP polypeptide which includes a motif or domain, for example, alipocalin domain or an AMP-binding domain. Such a polypeptide portioncan be a functional portion of a FATP protein. The term “lipocalindomain” is an art recognized term and as used herein refers to aparticular domain present in FATP proteins. This domain is described asincluding regions of sequence homology as well as a common tertiarystructure represented as an eight stranded antiparallel beta-barrel.(see Banaszak, L. et al., Advances in Protein Chemistry, 45: 89-151).Many lipocalin domains can be identified structurally as a sequencecontained within the general formula:[DENG]-X-[DENQGSTARK]-X(0,2)-[DENQARK]-[LIVFY]-{CP}-G-{C}-W-[FYWLRH-X]-[LIVMTA],e.g., the lipocalin signature sequence or consensus pattern (SEQ ID NO:125). One skilled in the art will recognize that a lipocalin domain fora particular FATP protein can vary in sequence from this generalformula. A FATP lipocalin domain can be, for example, identical to thelipocalin signature sequence, or, can exhibit 60, 65, 70, 75, 80, 85,90, 95 or greater sequence percent identity in comparison to the generalformula provided that it still retains the necessary lipocalin bindingfunction.

[0200] For example, a lipocalin domain for each of the human FATPs,hsFATP1 (SEQ ID NO: 126), hsFATP2 (SEQ ID NO: 127), hsFATP3 (SEQ ID NO:128), hsFATP4 (SEQ ID NO: 129), hsFATP5 (SEQ ID NO: 130), and hsFATP6(SEQ ID NO: 131) has been identified. These particular lipocalin domainsare located near the N-terminal portion of the specified proteins (seeFIG. 118). The sequences of these lipocalin domains are highly conservedacross the FATP family. A search using the lipocalin signature sequenceconducted on a public database (worldwide web at ebi.ac.uk/interpro/),indicated that the lipocalin domains of hsFATP1 and hsFATP4 shareidentity with signature sequence. In addition, a search directed toidentifying sequences having at least 80% identity to the lipocalinsignature sequence identified three additional human FATPs, hsFATP3,hsFATP5 and hsFATP6.

[0201] A lipocalin domain can also be identified functionally since, forexample, it has been identified as a binding motif capable of bindingfatty acids. In particular, the studies described in Experiment 20demonstrated that fusion proteins including the lipocalin domains fromhsFATP4 bound long chain fatty acids such as oleates and palmitates withgreat specificity. Other fatty acids can also be used to assess bindingin FATP4 and other members of the FATP family.

[0202] Polypeptides, including fusion polypeptides, which contain alipocalin domain can also include additional components. For example,fusion polypeptides containing a lipocalin domain can include amino acidresidues from the portion of the protein which is located upstream, i.e., in the direction of the N-terminal end of a FATP protein, from thelipocalin domain. As the term “upstream sequences” is used herein inrelation to the lipocalin domain, it is intended to refer to the aminoacid residues of a FATP protein which are located between the signalpeptide (when one is present) and the lipocalin domain. In the absenceof a signal peptide, the term refers to the portion of a FATP proteinbetween the lipocalin domain and the amino terminus (see FIG. 115).

[0203] Fusion polypeptides which contain a lipocalin domain can alsoinclude additional domains or motifs, for example, an AMP binding domaincan be included. For example, an AMP binding domain for each of thehuman FATPs, hsFATP1 (SEQ ID NO: 132), hsFATP2 (SEQ ID NO: 133), hsFATP3(SEQ ID NO: 134), hsFATP4 (SEQ ID NO: 135), hsFATP5 (SEQ ID NO: 136) andhsFATP6 (SEQ ID NO: 137) has been identified (see FIG. 118).

[0204] In one embodiment, the fusion protein can be immobilized on asuitable affinity matrix under conditions sufficient to bind theaffinity ligand portion of the fusion protein to the matrix, and iscontacted with one or more candidate binding agents (e.g., a mixture ofpeptides) to be tested, under conditions suitable for binding of thebinding agents to the FATP portion of the bound fusion protein. Next,the affinity matrix with bound fusion protein can be washed with asuitable wash buffer to remove unbound candidate binding agents andnon-specifically bound candidate binding agents. Those agents whichremain bound can be released by contacting the affinity matrix withfusion protein bound thereto with a suitable elution buffer. Wash buffercan be formulated to permit binding of the fusion protein to theaffinity matrix, without significantly disrupting binding ofspecifically bound binding agents. In this aspect, elution buffer can beformulated to permit retention of the fusion protein by the affinitymatrix, but can be formulated to interfere with binding of the candidatebinding agents to the target portion of the fusion protein. For example,a change in the ionic strength or pH of the elution buffer can lead torelease of specifically bound agent, or the elution buffer can comprisea release component or components designed to disrupt binding ofspecifically bound agent to the target portion of the fusion protein.

[0205] Immobilization can be performed prior to, simultaneous with, orafter, contacting the fusion protein with candidate binding agent, asappropriate. Various permutations of the method are possible, dependingupon factors such as the candidate molecules tested, the affinitymatrix-ligand pair selected, and elution buffer formulation. Forexample, after the wash step, fusion protein with binding agentmolecules bound thereto can be eluted from the affinity matrix with asuitable elution buffer (a matrix elution buffer, such as glutathionefor a GST fusion). Where the fusion protein comprises a cleavablelinker, such as a thrombin cleavage site, cleavage from the affinityligand can release a portion of the fusion with the candidate agentbound thereto. Bound agent molecules can then be released from thefusion protein or its cleavage product by an appropriate method, such asextraction.

[0206] One or more candidate binding agents can be testedsimultaneously. Where a mixture of candidate binding agents is tested,those found to bind by the foregoing processes can be separated (asappropriate) and identified by suitable methods (e.g., PCR, sequencing,chromatography). Large libraries of candidate binding agents (e.g.,peptides, RNA oligonucleotides) produced by combinatorial chemicalsynthesis or by other methods can be tested (see e.g., Ohlmeyer, M. H.J. et al., Proc. Natl. Acad. Sci. USA 90:10922-10926 (1993) and DeWitt,S. H. et al., Proc. Natl. Acad. Sci. USA 90:6909-6913 (1993), relatingto tagged compounds; see also Rutter, W. J. et al. U.S. Pat. No.5,010,175; Huebner, V. D. et al., U.S. Pat. No. 5,182,366; and Geysen,H. M., U.S. Pat. No. 4,833,092). Random sequence RNA libraries (seeEllington, A. D. et al., Nature 346:818-822 (1990); Bock, L. C. et al.,Nature 355:584-566 (1992); and Szostak, J. W., Trends in Biochem. Sci.17:89-93 (March, 1992)) can also be screened according to the presentmethod to select RNA molecules which bind to a target FATP or FATPfusion protein. Where binding agents selected from a combinatoriallibrary by the present method carry unique tags, identification ofindividual biomolecules by chromatographic methods is possible. Wherebinding agents do not carry tags, chromatographic separation, followedby mass spectrometry to ascertain structure, can be used to identifybinding agents selected by the method, for example.

[0207] The invention also comprises a method for identifying an agentwhich inhibits interaction between a fatty acid transport protein (e.g.,one comprising the amino acid sequence in SEQ ID NO:47, SEQ ID NO:49,SEQ ID NO:117, SEQ ID NO:53, SEQ ID NO:55, or SEQ ID NO:57), and aligand of said protein. The FATP can be one described by an amino acidsequence herein, a portion or fragment thereof, a variant thereof, or anortholog thereof, or a FATP fusion protein. Here, a ligand can be, forinstance, a substrate, or a substrate mimic, an antibody, or a compound,such as a peptide, that binds with specificity to a site on the protein.The method comprises combining, not limited to a particular order, thefatty acid protein, the ligand of the protein, and a candidate agent tobe assessed for its ability to inhibit interaction between the proteinand the ligand, under conditions appropriate for interaction between theprotein and the ligand (e.g., pH, salt, temperature conditions conduciveto appropriate conformation and molecular interactions); determining theextent to which the protein and ligand interact; and comparing (1) theextent of protein-ligand interaction in the presence of candidate agentwith (2) the extent of protein-ligand interaction in the absence ofcandidate agent, wherein if (1) is less than (2), then the candidateagent is one which inhibits interaction between the protein and theligand.

[0208] The method can be facilitated, for example, by using anexperimental system which employs a solid support (column chromatographymatrix, wall of a plate, microtiter wells, column pore glass, pins to besubmerged in a solution, beads, etc.) to which the protein can beattached. Accordingly, in one embodiment, the protein can be fixed to asolid phase directly or indirectly, by a linker. The candidate agent tobe tested is added under conditions conducive for interaction andbinding to the protein. The ligand is added to the solid phase systemunder conditions appropriate for binding. Excess ligand is removed, asby a series of washes done under conditions that do not disruptprotein-ligand interactions. Detection of bound ligand can befacilitated by using a ligand that carries a label (e.g., fluorescent,chemiluminescent, radioactive). In a control experiment, protein andligand are allowed to interact in the absence of any candidate agent,under conditions otherwise identical to those used for the “test”conditions where candidate inhibiting agent is present, and any washesused in the test conditions are also used in the control. The extent towhich ligand binds to the protein in the presence of candidate agent iscompared to the extent to which ligand binds to the protein in theabsence of the candidate agent. If the extent to which interaction ofthe protein and the ligand occurs is less in the presence of thecandidate agent than in the absence of the candidate agent, thecandidate agent is an agent which inhibits interaction between theprotein and the ligand of the protein.

[0209] In a further embodiment, an inhibitor (or an enhancer) of a fattyacid transport protein can be identified. The method comprises stepswhich are, or are variations of the following: contacting the cells withfatty acid, wherein the fatty acid can be labeled for convenience ofdetection; contacting a first aliquot of the cells with an agent beingtested as an inhibitor (or enhancer) of fatty acid uptake whilemaintaining a second aliquot of cells under the same conditions butwithout contact with the agent; and measuring (e.g., quantitating) fattyacid in the first and second aliquots of cells; wherein a lesserquantity of fatty acid in the first aliquot compared to that in thesecond aliquot is indicative that the agent is an inhibitor of fattyacid uptake by a fatty acid transport protein. A greater quantity offatty acid in the first aliquot compared to that in the second aliquotis indicative that the agent is an enhancer of fatty acid uptake by afatty acid transport protein.

[0210] A particular embodiment of identifying an inhibitor or enhancerof fatty acid transport function employs the above steps, but alsoemploys additional steps preceding those given above: introducing intocells of a cell strain or cell line (“host cells” for the intendedintroduction of, or after the introduction of, a vector) a vectorcomprising a fatty acid transport protein gene, wherein expression ofthe gene can be regulatable or constitutive, and providing conditions tothe host cells under which expression of the gene can occur.

[0211] The terms “contacting” and “combining” as used herein in thecontext of bringing molecules into close proximity to each other, can beaccomplished by conventional means. For example, when referring tomolecules that are soluble, contacting is achieved by adding themolecules together in a solution. “Contacting” can also be adding anagent to a test system, such as a vessel containing cells in tissueculture.

[0212] The term “inhibitor” or “antagonist”, as used herein, refers toan agent which blocks, diminishes, inhibits, hinders, limits, decreases,reduces, restricts or interferes with fatty acid transport into thecytoplasm of a cell, or alternatively and additionally, prevents orimpedes the cellular effects associated with fatty acid transport. Theterm “enhancer” or “agonist”, as used herein, refers to an agent whichaugments, enhances, or increases fatty acid transport into the cytoplasmof a cell. An antagonist will decrease fatty acid concentration, fattyacid metabolism and byproduct levels in the cell, leading to phenotypicand molecular changes.

[0213] In order to produce a “host cell” type suitable for fatty aciduptake assays and for assays derived therefrom for identifyinginhibitors or enhancers thereof, a nucleic acid vector can beconstructed to comprise a gene encoding a fatty acid transport protein,for example, human FATP1, FATP2, FATP3, FATP4, FATP5, FATP6, a mutant orvariant thereof, an ortholog of the human proteins, such as mouseorthologs or orthologs found in other mammals, or a FATP family proteinof origin in an organism other than a mammal. The gene of the vector canbe regulatable, such as by the placement of the gene under the controlof an inducible or repressible promoter in the vector (e.g., inducibleor repressible by a change in growth conditions of the host cellharboring the vector, such as addition of inducer, binding or functionalremoval of repressor from the cell millieu, or change in temperature)such that expression of the FATP gene can be turned on or initiated bycausing a change in growth conditions, thereby causing the proteinencoded by the gene to be produced, in host cells comprising the vector,as a plasma membrane protein. Alternatively, the FATP gene can beconstitutively expressed.

[0214] A vector comprising a FATP gene, such as a vector describedherein, can be introduced into host cells by a means appropriate to thevector and to the host cell type. For example, commonly used methodssuch as electroporation, transfection, for instance, transfection usingCaCl₂, and transduction (as for a virus or bacteriophage) can be used.Host cells can be, for example, mammalian cells such as primary culturecells or cells of cell lines such as COS cells, 293 cells or Jurkatcells. Host cells can also be, in some cases, cells derived frominsects, cells of insect cell lines, bacterial cells, such as E. coli,or yeast cells, such as S. cerevisiae. It is preferred that the fattyacid transport protein whose function is to be assessed, with or withouta candidate inhibitor or enhancer, be produced in host cells whoseancestor cells originated in a species related to the species of originof the FATP gene encoding the fatty acid transport protein. For example,it is preferable that tests of function or of inhibition or enhancementof a mammalian FATP be carried out in host mammalian cells producing theFATP, rather than bacterial cells or yeast cells.

[0215] Host cells comprising a vector comprising a regulatable FATP genecan be treated so as to allow expression of the FATP gene and productionof the encoded protein (e.g., by contacting the cells with an inducercompound that effects transcription from an inducible promoter operablylinked to the FATP gene).

[0216] Alternatively, host cells containing an endogenous FATP gene canbe engineered to activate or deactivate expression of the FATP gene andproduction of the encoded protein. For example, homologousrecombination, often referred to as targeting, can be utilized to alterthe regulatory region associated with the FATP gene to increase ordecrease the level of expression. Alteration of the regulatory regioncan include disablement of the regulatory region associated with theFATP gene and/or replacement of the region or a portion of the region. Avariety of regulatory regions are known which can be transfected intocells to cause an endogenous gene to display a pattern of induction orexpression that differs from that of the cell prior to transfection.

[0217] The test agent (e.g., an agonist or antagonist) is added to thecells to be used in a fatty acid transport assay, in the presence orabsence of test agent, under conditions suitable for production and/ormaintenance of the expressed FATP in a conformation appropriate forassociation of the FATP with test agent and substrate. For example,conditions under which an agent is assessed, such as media andtemperature requirements, can, initially, be similar to those necessaryfor transport of typical fatty acid substrates across the plasmamembrane. One of ordinary skill in the art will know how to varyexperimental conditions depending upon the biochemical nature of thetest agent. The test agent can be added to the cells in the presence offatty acid, or in the absence of fatty acid substrate, with the fattyacid substrate being added following the addition of the test agent. Theconcentration at which the test agent can be evaluated can be varied, asappropriate, to test for an increased effect with increasingconcentrations.

[0218] Test agents to be assessed for their effects on fatty acidtransport can be any chemical (element, molecule, compound), madesynthetically, made by recombinant techniques or isolated from a naturalsource. For example, test agents can be peptides, polypeptides,peptoids, sugars, hormones, or nucleic acid molecules, such as antisensenucleic acid molecules. In addition, test agents can be small moleculesor molecules of greater complexity made by combinatorial chemistry, forexample, and compiled into libraries. These libraries can comprise, forexample, alcohols, alkyl halides, amines, amides, esters, aldehydes,ethers and other classes of organic compounds. Test agents can also benatural or genetically engineered products isolated from lysates ofcells, bacterial, animal or plant, or can be the cell lysatesthemselves. Presentation of test compounds to the test system can be ineither an isolated form or as mixtures of compounds, especially ininitial screening steps.

[0219] Thus, the invention relates to a method for identifying agentswhich alter fatty acid transport, the method comprising providing thetest agent to the cell (wherein “cell” includes the plural, and caninclude cells of a cell strain, cell line or culture of primary cells ororgan culture, for example), under conditions suitable for binding toits target, whether to the FATP itself or to another target on or in thecell, wherein the transformed cell comprises a FATP.

[0220] In greater detail, to test one or more agents or compounds (e.g.,a mixture of compounds can conveniently be screened initially) forinhibition of the transport function of a fatty acid transport protein,the agent(s) can be contacted with the cells. The cells can be contactedwith a labeled fatty acid. The fatty acid can be, for example, a knownsubstrate of the fatty acid transport protein such as oleate orpalmitate. The fatty acid can itself be labeled with a radioactiveisotope, (e.g., ³H or 14C) or can have a radioactively labeled adductattached. In other variations, the fatty acid can have chemicallyattached to it a fluorescent label, or a substrate for an enzymeoccurring within the cells, wherein the substrate yields a detectableproduct, such as a highly colored or fluorescent product. Addition ofcandidate inhibitors and labeled substrate to the cells comprising fattyacid transport protein can be in either order or can be simultaneous.

[0221] A second aliquot of cells, which can be called “control” cells (a“first” aliquot of cells can be called “test” cells), is treated, ifnecessary (as in the case of transformed “host” cells), so as to allowexpression of the FATP gene, and is contacted with the labeled substrateof the fatty acid transport protein. The second aliquot of cells is notcontacted with one or more agents to be tested for inhibition of thetransport function of the protein produced in the cells, but isotherwise kept under the same culture conditions as the first aliquot ofcells.

[0222] In a further step of a method to identify inhibitors of a fattyacid transport protein, the labeled fatty acid is measured in the firstand second aliquots of cells. A preliminary step of this measurementprocess can be to separate the external medium from the cells so as tobe able to distinguish the labeled fatty acid external to the cells fromthat which has been transported inside the cells. This can beaccomplished, for instance, by removing the cells from their growthcontainer, centrifuging the cell suspension, removing the supernatantand performing one or more wash steps to extensively dilute theremaining medium which may contain labeled fatty acid. Detection of thelabeled fatty acid can be by a means appropriate to the label used. Forexample, for a radioactive label, detection can be by scintillationcounting of appropriately prepared samples of cells (e.g., lysates orprotein extracts); for a fluorescent label, by measuring fluorescence inthe cells by appropriate instrumentation.

[0223] If a compound tested as a candidate inhibitor of transportfunction causes the test cells to have less labeled fatty acid detectedin the cells than that detected in the control cells, then the compoundis an inhibitor of the fatty acid transport protein. Proceduresanalogous to those above can be devised for identifying enhancers(agonists of FATPs) of fatty acid transport function wherein if the testcells contain more labeled fatty acid than that detected in the controlcells, or if the fatty acid is taken up at a higher rate, then thecompound being tested can be concluded to be an enhancer of the fattyacid transport protein.

[0224] Example 13 describes use of an assay of this type to identify aninhibitor of a FATP. In Example 13, an antisense oligonucleotide whichspecifically inhibits biosynthesis of mmFATP4 was demonstrated toinhibit fatty acid uptake into mouse enterocytes. Similarly, antisenseoligonucleotides directed towards specifically inhibiting thebiosynthesis of FATP6 in heart cells, FATP5 in liver cells, FATP3 inlung cells, and FATP2 in colon cells, can be demonstrated as examples of“test agents” that inhibit fatty acid transport.

[0225] Another assay to determine whether an agent is an inhibitor (orenhancer) of fatty acid transport employs animals, one or more of whichare administered the agent, and one or more of which are maintainedunder similar conditions, but are not administered the agent. Bothgroups of animals are given fatty acids (e.g., orally, intravenously, bytube inserted into stomach or intestine), and the fatty acids taken upinto a bodily fluid (e.g., serum) or into an organ or tissue of interestare measured from comparable samples taken from each group of animals.The fatty acids may carry a label (e.g., radioactive) to facilitatedetection and quantitation of fatty acids taken up into the fluid ortissue being sampled. This type of assay can be used alone or can beused in addition to in vitro assays of a candidate inhibitor orenhancer.

[0226] An agent determined to be an inhibitor (or enhancer) of FATPfunction, such as fatty acid binding and/or fatty acid uptake, can beadministered to cells in culture, or in vivo, to a mammal (e.g. human)to inhibit (or enhance) FATP function. Such an agent may be one thatacts directly on the FATP (for example, by binding) or can act on anintermediate in a biosynthetic pathway to produce FATP, such astranscription of the FATP gene, processing of the mRNA, or translationof the mRNA. An example of such an agent is antisense oligonucleotide.

[0227] Antisense methods similar to those illustrated in Example 13 canbe used to determine the target FATP of a compound or agent that has aninhibitory or enhancing effect on fatty acid uptake. For example,antisense oligonucleotide directed to the inhibition of FATP4biosynthesis can be added to lung cells or cell lines derived from lungcells. In addition, antisense oligonucleotides directed to theinhibition of other FATPs, except for FATP3, can also be added to thelung cells. The administration of antisense oligonucleotides in thismanner ensures that the predominant FATP activity remaining in the cellscomes from FATP3. After a period of incubation of the cells with theantisense oligonucleotides sufficient to deplete the plasma membrane ofthe FATPs whose biosynthesis has been inhibited, a test agent,preferably one that has been shown by some preliminary test to have aninhibitory or enhancing activity on fatty acid transport, can be addedto the lung cells. If the test agent is now demonstrated, aftertreatment of the cells with antisense oligonucleotides, to have aninhibitory or enhancing activity on fatty acid transport in the lungcells, it can be concluded that the target of the test agent is FATP3,or a molecule involved in the biosynthesis or activity of FATP3.

[0228] In another type of cell-based assay for uptake of fatty acids, achange of intracellular pH resulting from the uptake of fatty acids canbe followed by an indicator fluorophore. The fluorophore can be taken upby the cells in a preincubation step. Fatty acids can be added to thecell medium, and after some period of incubation to allow FATP-mediateduptake of fatty acids, the change in λ_(max) of fluorescence can bemeasured, as an indicator of a change in intracellular pH, as theλ_(max) of fluorescence of the fluorophore changes with the pH of itsenvironment, thereby indicating uptake of fatty acids. One suchfluorophore is BCECF (2′,7′-bis(2-carboxyethyl)-5(6)-carboxyfluorescein; Rink, T. J. et al., JCell. Biol. 95: 189 (1982)).

[0229] In assays similar to those described above, a candidate inhibitoror enhancer of fatty acid transport function can be added (ormock-added, for control cultures) to cultures of cells engineered toexpress a desired FATP to which fatty acid substrate is also added.Inhibition of fatty acid uptake is indicated by a lack of the drop inpH, indicating fatty acid uptake, that is seen in control cells.Enhancement of fatty acid uptake is indicated by a decrease inintracellular pH, as compared to control cells not receiving thecandidate enhancer of fatty acid transport function.

[0230] Yeast cells can be used in a similar cell-based assay for theuptake of fatty acids mediated by a FATP, and such an assay can beadapted to a screening assay for the identification of agents thatinhibit or enhance fatty acid uptake by an FATP. Yeast cells lacking anendogenous FATP activity (mutated, disrupted or deleted for FAT1;Faergeman, N. J. et al., J. Biol. Chem. 272(13):8531-8538 (1997);Watkins, P. A. et al., J. Biol. Chem. 273(29):18210-18219 (1998)) can beengineered to harbor a related gene of the family of FATP-encodinggenes, such as a mammalian FATP (e.g., human FATP4).

[0231] Examples of expression vectors include pEG (Mitchell, D. A., etal., Yeast 9:715-723 (1993)) and pDAD1 and pDAD2, which contain a GAL1promoter (Davis, L. I. and Fink, G. R., Cell 61:965-978 (1990)). Avariety of promoters are suitable for expression. Available yeastvectors offer a choice of promoters. In one embodiment, the inducibleGAL1 promoter is used. In another embodiment, the constitutive ADH1promoter (alcohol dehydrogenase; Bennetzen, J. L. and Hall, B. D., J.Biol. Chem. 257:3026-3031 (1982)) can be used to express an insertedgene on glucose-containing media. An example of a vector suitable forexpression of a heterologous FATP gene in yeast is pQB169.

[0232] With the introduced FATP gene providing the only fatty acidtransport protein function for the yeast cells, it is possible to studyeffect of the heterologous FATP on fatty acid transport into the yeastcells in isolation. Assays for the uptake of fatty acids into the yeastcells can be devised that are similar to those described above and/orthose assays that have been illustrated in the Examples. Tests forcandidate inhibitors or enhancers of the heterologous FATP can be donein cultures of yeast cells, wherein the yeast cells are incubated withfatty acid substrate and an agent to be tested as an inhibitor orenhancer of FATP function. FATP uptake after a period of time can bemeasured by analyzing the contents of the yeast cells for fatty acidsubstrate, as compared with control yeast cells incubated with the fattyacid, but not with the test agent. Yeast cells have the additionaladvantage, over mammalian cells in culture, for example, that yeastcells can be forced to rely upon fatty acids as their only source ofcarbon, if the growth medium supplied to the yeast cells is formulatedto contain no other source of carbon. Thus, the effect of theheterologous FATP on fatty acid uptake and metabolism in the engineeredyeast cells can be amplified. An agent that efficiently blocks transportfunction of the heterologous FATP could result in death of the yeastcells. Thus, in this case, inhibition of function of the heterologousFATP can result in loss of viability. A simple measure of viability isturbidity of the yeast suspension culture, which can be adapted to ahigh throughput screening assay for effects of various agents to betested, using microtiter plates or similar devices for small-volumecultures of the engineered yeast cells.

[0233] Cell-free assays can also be used to measure the transport offatty acids across a membrane, and therefor also to assess a testtreatment or test agent for its effect on the rate or extent of fattyacid transport. An isolated FATP, for example in the presence of adetergent that preserves the native 3-dimensional structure of the FATP,or partially purified FATP, can be used in an artificial membrane systemtypically used to preserve the native conformation and activity ofmembrane proteins. Such systems include liposomes, artificial bilayersof phospholipids, isolated plasma membrane such as cell membranefragments, cell membrane fractions, or cell membrane vesicles, and othersystems in which the FATP can be properly oriented within the membraneto have transport activity. Assays for transport activity can beperformed using methods analogous to those that can be used in cellsengineered to predominantly express one FATP whose function is to bemeasured. A labeled (e.g., radioactively labeled) fatty acid substratecan be incubated with one side of a bilayer or in a suspension ofliposomes constructed to integrate a properly oriented FATP. Theaccumulation of fatty acids with time can be measured, using appropriatemeans to detect the label (e.g., scintillation counting of medium oneach side of the bilayer, or of the contents of liposomes isolated fromthe surrounding medium). Assays such as these can be adapted to use forthe testing of agents which might interact with the FATP to produce aninhibitory or an enhancing effect on the rate or extent of fatty acidtransport. That is, the above-described assay can be done in thepresence or absence of the agent to be tested, and the results compared.

[0234] For examples of isolation of membrane proteins (ADP/ATP carrierand uncoupling protein), reconstitution into phospholipid vesicles, andassays of transport, see Klingenberg, M. et al., Methods Enzymol.260:369-389 (1995). For an example of a membrane protein (phosphatecarrier of Saccharomyces cerevisiae) that was purified and solubilizedfrom E. coli inclusion bodies, see Schroer, A. et al., J. Biol. Chem.273: 14269-14276 (1998). The Glut1 glucose transporter of rat has beenexpressed in yeast. A crude membrane fraction of the yeast was preparedand reconstituted with soybean phospholipids into liposomes. Glucosetransport activity could be measured in the liposomes (Kasahara, T. andKasahara, M., J. Biol. Chem. 273: 29113-29117 (1998)). Similar methodscan be applied to the proteins and polypeptides of the invention.

[0235] Another embodiment of the invention is a method for inhibitingfatty acid uptake in a mammal (e.g., a human), comprising administeringto the mammal a therapeutically effective amount of an inhibitor of thetransport function of one or more of the fatty acid transport proteins,thereby decreasing fatty acid uptake by cells comprising the fatty acidprotein(s). Where it is desirable to reduce the uptake of fatty acids,for example, in the treatment of chronic obesity or as a part of aprogram of weight control or hyperlipidemia control in a human, one ormore inhibitors of one or more of the fatty acid transport proteins canbe administered in an effective dose, and by an effective route, forexample, orally, or by an indwelling device that can deliver doses tothe small intestine. The inhibitor can be one identified by methodsdescribed herein, or can be one that is, for instance, structurallyrelated to an inhibitor identified by methods described herein (e.g.,having chemical adducts to better stabilize or solubilize theinhibitor). The invention further relates to compositions comprisinginhibitors of fatty acid uptake in a mammal, which may further comprisepharmaceutical carriers suitable for administration to a subject mammal,such as sterile solubilizing or emulsifying agents.

[0236] A further embodiment of the present invention is a method ofenhancing or increasing fatty acid uptake, such as enhancing orincreasing LCFA uptake in the small intestine (e.g., to treat or preventa malabsorption syndrome or other wasting condition) or in the liver(e.g., by an enhancer of FATP5 transport activity to treat acute liverfailure) or in the kidney (e.g., by an enhancer of FATP2 transportactivity to treat kidney failure). In this embodiment, a therapeuticallyeffective amount of an enhancer of the transport function of one or moreof the fatty acid transport proteins can be administered to a mammaliansubject, with the result that fatty acid uptake in the small intestineis enhanced. In this embodiment, one or more enhancers of one or more offatty acid transport proteins is administered in an effective dose andby a route (e.g., orally or by a device, such as an indwelling catheteror other device) which can deliver doses to the gut. The enhancer ofFATP function (e.g., an enhancer of FATP4 function) can be identified bymethods described herein or can be one that is structurally similar toan enhancer identified by methods described herein.

[0237] Aerobic reperfusion of ischemic myocardium is a common clinicalevent which can occur during such treatments as cardiac surgery,angioplasty, and thrombolytic therapy after a myocardial infarction.During reperfusion, a rapid recovery of myocardial energy production isessential for the complete recovery of contractile function. Not onlythe extent of recovery of myocardial energy metabolism but also the typeof energy substrate used by the heart during reperfusion are importantdeterminants of functional recovery. Circulating fatty acid levelsincrease following acute myocardial infarction or during cardiacsurgery, such that during and following ischemia the heart muscle can beexposed to very high concentrations of fatty acids (Lopaschuk, G. D. andW. C. Stanley, Science and Medicine (November/December 1997)). Highplasma fatty acid concentrations increase the severity of ischemicdamage in a number of experimental models of cardiac ischemia and havebeen linked to depression of mechanical function during aerobicreperfusion of previously ischemic hearts. Further data show thatmodifying fatty acid utilization can be beneficial for heart function inischemia and can be a useful approach for the treatment of angina. See,e.g., Desideri and Celegon, Am. J. Cardiol. 82(5A):50K-53K; Lopaschuk,Am. J. Cardiol. 82(5A):14K-1 7K. Plasma fatty acid concentrations can bereduced by administering to a human subject or other mammal an effectiveamount of an inhibitor of a FATP such as FATP2 or FATP4, therebyproviding a way of reducing fatty acid utilization by the heart.

[0238] In a further embodiment of the invention, a therapeuticallyeffective amount of an inhibitor of hsFATP6 can be administered to ahuman patient by a suitable route, to reduce the uptake of fatty acidsby cardiac muscle. This treatment is desirable in patients who arediagnosed as having, or who are at risk of, abnormal accumulations offatty acids in the heart or a detrimentally high rate of uptake of fattyacids into the heart, because of ischemic heart disease, or followingischemia or trauma to the heart.

[0239] The invention further relates to antibodies that bind to anisolated or recombinant fatty acid transport protein of the FATP family,including portions of antibodies, which can specifically recognize andbind to one or more FATPs. The antibodies and portions thereof of theinvention include those which bind to one or more FATPs of mouse orother mammalian species. In a preferred embodiment, the antibodiesspecifically bind to a naturally occurring FATP of humans. Theantibodies can be used in methods to detect or to purify a protein ofthe present invention or a portion thereof by various methods ofimmunoaffinity chromatography, to inhibit the function of a protein in amethod of therapy, or to selectively inactivate an active site, or tostudy other aspects of the structure of these proteins, for example.

[0240] The antibodies of the present invention can be polyclonal ormonoclonal. The term antibody is intended to encompass both polyclonaland monoclonal antibodies. Antibodies of the present invention can beraised against an appropriate immunogen, including proteins orpolypeptides of the present invention, such as an isolated orrecombinant FATP1, FATP2, FATP3, FATP4, FATP5, FATP6, mtFATP, ceFATPa,ceFATPb, scFATP or portions thereof, or synthetic molecules, such assynthetic peptides (e.g., conjugated to a suitable carrier). Preferredembodiments are antibodies that bind to any of the following: hsFATP 1,hsFATP2, hsFATP3, hsFATP4, hsFATP5 or hsFATP6. The immunogen can be apolypeptide comprising a portion of a FATP and having at least onefunction of a fatty acid transport protein, as described herein.

[0241] The term antibody is also intended to encompass single chainantibodies, chimeric, humanized or primatized (CDR-grafted) antibodiesand the like, as well as chimeric or CDR-grafted single chainantibodies, comprising portions from more than one species. For example,the chimeric antibodies can comprise portions of proteins derived fromtwo different species, joined together chemically by conventionaltechniques or prepared as a single contiguous protein using, geneticengineering techniques (e.g., DNA encoding the protein portions of thechimeric antibody can be expressed to produce a contiguous proteinchain. See, e.g., Cabilly et al., U.S. Pat. No. 4,816,567; Cabilly etal., European Patent No. 0,125,023 B1; Boss et al., U.S. Pat. No.4,816,397; Boss et al., European Patent No. 0,120,694 B1; Neuberger, M.S. et al., WO 86/01533; Neuberger, M. S. et al., European Patent No.0,194,276 B1; Winter, U.S. Pat. No. 5,225,539; Winter, European PatentNo. 0,239,400 B1; Queen et al., U.S. Pat. No. 5,585,089; and Queen etal., European Patent No. EP 0 451 216 B1. See also, Newman, R. et al.,BioTechnology, 10: 1455-1460 (1992), regarding primatized antibody, andLadner et al., U.S. Pat. No. 4,946,778 and Bird, R. E. et al., Science,242:423-426 (1988) regarding single chain antibodies.)

[0242] Whole antibodies and biologically functional fragments thereofare also encompassed by the term antibody. Biologically functionalantibody fragments which can be used include those fragments sufficientfor binding of the antibody fragment to a FATP to occur, such as Fv,Fab, Fab′ and F(ab′)₂ fragments. Such fragments can be produced byenzymatic cleavage or by recombinant techniques. For instance, papain orpepsin cleavage can generate Fab or F(ab′)₂ fragments, respectively.Antibodies can also be produced in a variety of truncated forms usingantibody genes in which one or more stop codons have been introducedupstream of the natural stop site. For example, a chimeric gene encodinga F(ab′)₂ heavy chain portion can be designed to include DNA sequencesencoding the CH₁ domain and hinge region of the heavy chain.

[0243] Preparation of immunizing antigen (whole cells comprising FATP onthe cell surface or purified FATP), and polyclonal and monoclonalantibody production can be performed using any suitable technique. Avariety of methods have been described (See e.g., Kohler et al., Nature,256: 495-497 (1975) and Eur. J. Immunol. 6: 511-519 (1976); Milstein etal., Nature 266: 550-552 (1977); Koprowski et al., U.S. Pat. No.4,172,124; Harlow, E. and D. Lane, 1988, Antibodies: A LaboratoryManual, (Cold Spring Harbor Laboratory: Cold Spring Harbor, N.Y.);Chapter 11 In Current Protocols In Molecular Biology, Vol. 2 (containingsupplements up through Supplement 42, 1998), Ausubel, F. M. et al.,eds., (John Wiley & Sons: New York, N.Y.)). Generally, a hybridoma canbe produced by fusing a suitable immortal cell line (e.g., a myelomacell line such as SP2/0) with antibody producing cells. The antibodyproducing cells, preferably those obtained from the spleen or lymphnodes, can be obtained from animals immunized with the antigen ofinterest. Immunization of animals can be by introduction of whole cellscomprising fatty acid transport protein on the cell surface. The fusedcells (hybridomas) can be isolated using selective culture conditions,and cloned by limiting dilution. Cells which produce antibodies with thedesired specificity can be selected by a suitable assay (e.g., ELISA).

[0244] Other suitable methods of producing or isolating antibodies(including human antibodies) of the requisite specificity can used,including, for example, methods which select recombinant antibody from alibrary (e.g., Hoogenboom et al., WO 93/06213; Hoogenboom et al., U.S.Pat. No. 5,565,332; WO 94/13804, published Jun. 23, 1994; and Dower, W.J. et al., U.S. Pat. No. 5,427,908), or which rely upon immunization oftransgenic animals (e.g., mice) capable of producing a full repertoireof human antibodies (see e.g., Jakobovits et al., Proc. Natl. Acad. Sci.USA, 90: 2551-2555 (1993); Jakobovits et al., Nature, 362:255-258(1993); Lonberg et al., U.S. Pat. No. 5,569,825; Lonberg et al., U.S.Pat. No. 5,545,806; Surani et al., U.S. Pat. No. 5,545,807; andKucherlapati, R. et al., European Patent No. EP 0 463 151 B1).

[0245] Another aspect of the invention is a method for directing anagent to cardiac muscle. The differential expression of FATP6 in cardiacmuscle but not in other tissue types allows for the specific targetingof drugs, diagnostic agents, tagging labels, histological stains orother substances specifically to cardiac muscle. A targeting vehicle canbe used for the delivery of such a substance. Targeting vehicles whichbind specifically to FATP6 can be linked to a substance to be deliveredto the cells of cardiac muscle. The linkage can be, for instance, viaone or more covalent bonds, or by high affinity non-covalent bonds. Atargeting vehicle can be an antibody, for instance, or other compound(e.g., a fatty acid or fatty acid analog) which binds to FATP6 with highspecificity.

[0246] Targeting vehicles specific to the heart-specific protein FATP6have in vivo (e.g., therapeutic and diagnostic) applications. Forexample, an antibody which specifically binds to FATP6 can be conjugatedto a drug to be targeted to the heart (e.g., a cardiac glycoside totreat congestive heart failure, or β-adrenergic agents, sodium channelblockers or calcium channel blockers to treat arrhythmias). A substance(e.g., a radioactive substance) which can be detected (e.g., a label) invivo can also be linked to a targeting vehicle which specifically bindsto a heart-specific protein such as FATP6, and the conjugate can be usedas a labeling agent to identify cardiac muscle cells.

[0247] Targeting vehicles specific to FATP6 find further applications invitro. For example, an FATP6-specific targeting vehicle, such as anantibody (a polyclonal preparation or monoclonal) which specificallybinds to FATP6, can be linked to a substance which can be used as astain for a tissue sample (e.g., horseradish peroxidase) to provide amethod for the identification of cardiac muscle in a sample, as can beused in embryology studies, for example.

[0248] In a similar manner, an agent can be directed to the liver of amammal, as FATP5 is expressed in liver but not in other tissue types. Atargeting vehicle which specifically binds to FATP5 can be conjugated toa drug for delivery of the drug to the liver, such as a drug to treathepatitis, Wilson's disease, lipid storage diseases and liver cancer. Aswith targeting vehicles specific to FATP6, targeting vehicles specificto FATP5 can be used in studying tissue samples in vitro.

[0249] The invention also relates to compositions comprising a modulatorof FATP function. The term “modulate” as used herein refers to theability of a molecule to alter the function of another molecule. Thus,modulate could mean, for example, inhibit, antagonize, agonize,upregulate, downregulate, induce, or suppress. A modulator has thecapability of altering function of its target. Such alteration can beaccomplished at any stage of the transcription, translation, expressionor function of the protein, so that, for example, modulation of a targetgene can be accomplished by modulation of the DNA or RNA encoding theprotein, and the protein itself.

[0250] Antagonists or agonists (inhibitors or enhancers) of the FATPs ofthe invention, antibodies that bind a FATP, or mimetics of a FATP can beemployed in combination with a non-sterile or sterile carrier orcarriers for use with cells, tissues or organisms, such as apharmaceutical carrier suitable for administration to a mammaliansubject. Such compositions comprise, for instance, a media additive or atherapeutically effective amount of an inhibitor or enhancer compound tobe identified by an assay of the invention and a pharmaceuticallyacceptable carrier or excipient. Such carriers may include, but are notlimited to, saline, buffered saline, dextrose, water, ethanol,surfactants, such as glycerol, excipients such as lactose andcombinations thereof. The formulation can be chosen by one of ordinaryskill in the art to suit the mode of administration. The chosen route ofadministration will be influenced by the predominant tissue or organlocation of the FATP whose function is to be inhibited or enhanced. Forexample, for affecting the function of FATP4, a preferred administrationcan be oral or through a tube inserted into the stomach (e.g., directstomach tube or nasopharyngeal tube), or through other means toaccomplish delivery to the small intestine. The invention furtherrelates to diagnostic and pharmaceutical packs and kits comprising oneor more containers filled with one or more of the ingredients of theaforementioned compositions of the invention.

[0251] Compounds of the invention which are FATPs, FATP fusion proteins,FATP mimetics, FATP gene-specific antisense poly- or oligonucleotides,inhibitors or enhancers of a FATP may be employed alone or inconjunction with other compounds, such as therapeutic compounds. Thepharmaceutical compositions may be administered in any effective,convenient manner, including administration by topical, oral, anal,vaginal, intravenous, intraperitoneal, intramuscular, subcutaneous,intranasal, transdermal or intradermal routes, among others. In therapyor as a prophylactic, the active agent may be administered to anindividual as an injectable composition, for example as a sterileaqueous dispersion, preferably isotonic.

[0252] Alternatively, the composition may be formulated for topicalapplication, for example, in the form of ointments, creams, lotions, eyeointments, eye drops, ear drops, mouthwash, impregnated dressings andsutures and aerosols, and may contain appropriate conventionaladditives, including, for example, preservatives, solvents to assistdrug penetration, and emollients in ointments and creams. Such topicalformulations may also contain compatible conventional carriers, forexample cream or ointment bases, and ethanol or oleyl alcohol forlotions.

[0253] In addition, the amount of the compound will vary depending onthe size, age, body weight, general health, sex, and diet of the host,and the time of administration, the biological half-life of thecompound, and the particular characteristics and symptoms of thedisorder to be treated. Adjustment and manipulation of established doseranges are well within the ability of those of skill in the art.

[0254] A further aspect of the invention is a method to identify apolymorphism, or the presence of an alternative or variant allele of agene in the genome of an organism (of interest here, genes encodingFATPs). As used herein, polymorphism refers to the occurrence of two ormore genetically determined alternative sequences or alleles in apopulation. A polymorphic locus may be as small as a base pair.Polymorphic markers include restriction fragment length polymorphisms,variable number of tandem repeats (VNTR's), hypervariable regions,minisatellites, dinucleotide repeats, trinucleotide repeats,tetranucleotide repeats, simple sequence repeats, and insertion elementssuch as Alu. The first identified alleleic form, or the most frequentlyoccurring form can be arbitrarily designated as the reference (usually,“wildtype”) form, and other allelic forms are designated as alternative(sometimes, “mutant” or “variant”). Dipolid organisms may be homozygousor heterozygous for allelic forms.

[0255] An “allele” or “allelic sequence” is an alternative form of agene which may result from at least one mutation in the nucleotidesequence. Alleles may result in altered mRNAs or polypeptides whosestructure or function may or may not be altered. Any given gene may havenone, one, or many allelic forms (polymorphism). Common mutationalchanges which give rise to alleles are generally ascribed to naturaldeletions, additions, or substitutions of nucleotides. Each of thesetypes of changes may occur alone, or in combination with the others, oneor more times in a given sequence.

[0256] Several different types of polymorphisms have been reported. Arestriction fragment length polymorphism (RFLP) is a variation in DNAsequence that alters the length of a restriction fragment (Botstein etal., Am. J. Hum. Genet. 32:314-331 (1980)). The restriction fragmentlength polymorphism may create or delete a restriction site, thuschanging the length of the restriction fragment. RFLPs have been widelyused in, human and animal genetic analyses (see WO 90/13668; WO90/11369; Donis-Keller, Cell 51:319-337 (1987); Lander et al., Genetics121:85-99 (1989)). When a heritable trait can be linked to a particularRFLP, the presence of the RFLP in an individual can be used to predictthe likelihood that the individual will also exhibit the trait.

[0257] Other polymorphisms take the form of short tandem repeats (STRs)that include tandem di-, tri- and tetra-nucleotide repeated motifs.These tandem repeats are also referred to as variable number tandemrepeat (VNTR) polymorphisms. VNTRs have been used in identity andpaternity analysis (U.S. Pat. No. 5,075,217; Armour et al., FEBS Lett.307:113-115 (1992); Horn et al., WO 91/14003; Jeffreys, EP 370,719), andin a large number of genetic mapping studies.

[0258] Other polymorphisms take the form of single nucleotide variationsbetween individuals of the same species. Such polymorphisms are far morefrequent than RFLPs, STRs (short tandem repeats) and VNTRs (variablenumber tandem repeats). Some single nucleotide polymorphisms occur inprotein-coding sequences, in which case, one of the polymorphic formsmay give rise to the expression of a defective or other variant proteinand, potentially, a genetic disease. Other single nucleotidepolymorphisms occur in noncoding regions. Some of these polymorphismsmay also result in defective protein expression (e.g., as a result ofdefective splicing). Other single nucleotide polymorphisms have nophenotypic effects.

[0259] Many of the methods described below require amplification of DNAfrom target samples and purification of the amplified products. This canbe accomplished by PCR, for instance. See generally, PCR Technology,Principles and Applications for DNA Amplification (ed. H. A. Erlich),Freeman Press, New York, N.Y., 1992; PCR Protocols. A Guide to Methodsand Applications (eds. Innis, et al.), Academic Press, San Diego,Calif., 1990; Mattila et al., Nucleic Acids Res. 19:4967 (1991); Eckertet al., PCR Methods and Applications 1:17 (1991); PCR (eds. McPherson etal., IRS Press, Oxford); and U.S. Pat. No. 4,683,202.

[0260] Other suitable amplification methods include the ligase chainreaction (LCR) (see Wu and Wallace, Genomics 4:560 (1989); Landegren etal., Science 241:1077 (1988)), transcription amplification (Kwoh et al.,Proc. Natl. Acad. Sci. USA 86:1173 (1989), self-sustained sequencereplication (Guatelli et al., Proc. Natl. Acad. Sci. USA 87:1874 (1990),and nucleic acid based sequence amplification (NASBA). The latter twoamplification methods involve isothermal reactions based on isothermaltranscription, which produce both single stranded RNA (ssRNA) and doublestranded DNA (dsDNA) as the amplification products in a ratio of about30 or 100 to 1, respectively.

[0261] Another aspect of the invention is a method for detecting avariant allele of a human FATP gene, comprising preparing amplified,purified FATP DNA from a reference human and amplified, purified, FATPDNA from a “test” human to be compared to the reference as having avariant allele, using the same or comparable amplification procedures,and determining whether the reference DNA and test DNA differ in DNAsequence in the FATP gene, whether in a coding or a noncoding region,wherein, if the test DNA differs in sequence from the reference DNA, thetest DNA comprises a variant allele of a human FATP gene. The followingis a discussion of some of the methods by which it can be determinedwhether the reference FATP DNA and test FATP DNA differ in sequence.

[0262] Direct Sequencing.

[0263] The direct analysis of the sequence of variant alleles of thepresent invention can be accomplished using either the dideoxy chaintermination method or the Maxam and Gilbert method (see Sambrook et al.,Molecular Cloning: A Laboratory Manual, 2nd ed., Cold Spring HarborPress, New York 1989; Zyskind et al., Recombinant DNA Laboratory Manual,Acad. Press, 1988)).

[0264] Denaturing Gradient Gel Electrophoresis.

[0265] Amplification products generated using the polymerase chainreaction can be analyzed by the use of denaturing gradient geleletrophoresis. Different alleles can be identified based on thedifferent sequence-dependent strand dissociation properties andelectrophoretic migration of DNA in solution (chapter 7 in Erlich, ed.PCR Technology, Principles and Applications for DNA Amplification, W. H.Freeman and Co., New York, 1992).

[0266] Single-Strand Conformation Polymorphism Analysis.

[0267] Alleles of target sequences can be differentiated usingsingle-strand conformation polymorphism analysis, which identifies basedifferences by alteration in electrophoretic migration of singlestranded PCR products, as described in Orita et al., Proc. Natl. Acad.Sci. USA 86:2766-2770 (1989). Amplified PCR products can be generated asdescribed above, and heated or otherwise denatured, to formsingle-stranded amplification products. Single-stranded nucleic acidsmay refold or form secondary structures which are partially dependent onthe base sequence. The different electrophoretic mobilities ofsingle-stranded amplification products can be related to base-sequencedifferences between alleles of target sequences.

[0268] Detection of Binding by Protein that Binds to Mismatches.

[0269] Amplified DNA comprising the FATP gene or portion of the gene ofinterest from genomic DNA, for example, of a normal individual isprepared, using primers designed on the basis of the DNA sequencesprovided herein. Amplified DNA is also prepared, in a similar manner,from genomic DNA of an individual to be tested for bearing adistinguishable allele. The primers used in PCR carry different labels,for example, primer 1 with biotin, and primer 2 with ³²P. Unused primersare separated from the PCR products, and the products are quantitated.The heteroduplexes are used in a mismatch detection assay usingimmobilized mismatch binding protein (MutS) bound to nitrocellulose. Thepresence of biotin-labeled DNA wherein mismatched regions are bound tothe nitrocellulose via MutS protein, is detected by visualizing thebinding of streptavidin to biotin. See WO 95/12689. MutS protein hasalso been used in the detection of point mutations in agel-mobility-shift assay (Lishanski, A. et al., Proc. Natl. Acad. Sci.USA 91:2674-2678 (1994)).

[0270] Other methods, such as those described below, can be used todistinguish a FATP allele from a reference allele, once a particularallele has been characterized as to DNA sequence.

[0271] Allele-Specific Probes.

[0272] The design and use of allele-specific probes for analyzingpolymorphims is described by e.g., Saiki et al., Nature 324:163-166(1986); Dattagupta, EP 235,726, Saiki, WO 89/11548. Allele-specificprobes can be designed so that they hybridize to a segment of a targetDNA from one individual but do not hybridize to the correspondingsegment from another individual due to the presence of differentpolymorphic forms in the respective segments from the two individuals.Hybridization conditions should be sufficiently stringent that there isa significant difference in hybridization intensity between alleles, andpreferably an essentially binary response, whereby a probe hybridizes toonly one of the alleles. Some probes are designed to hybridize to asegment of target DNA such that the polymorphic site aligns with acentral position (e.g., in a 15-mer at the 7 position; in a 16-mer, ateither the 8 or 9 position) of the probe. This design of probe achievesgood discrimination in hybridization between different allelic forms.

[0273] Allele-specific probes are often used in pairs, one member of apair showing a perfect match to a reference form of a target sequenceand the other member showing a perfect match to a variant form. Severalpairs of probes can then be immobilized on the same support forsimultaneous analysis of multiple polymorphisms within the same targetsequence.

[0274] Allele-Specific Primers.

[0275] An allele-specific primer hybridizes to a site on target DNAoverlapping a polymorphism, and only primes amplification of an allelicform to which the primer exhibits perfect complementarity. See Gibbs,Nucleic Acid Res. 17:2427-2448 (1989). This primer is used inconjunction with a second primer which hybridizes at a distal site.Amplification proceeds from the two primers, resulting in a detectableproduct which indicates the particular allelic form is present. Acontrol is usually performed with a second pair of primers, one of whichshows a single base mismatch at the polymorphic site and the other ofwhich exhibits perfect complementarity to a distal site. The single-basemismatch prevents amplification and no detectable product is formed. Themethod works best when the mismatch is included in the 3′-most positionof the oligonucleotide aligned with the polymorphism because thisposition is most destabilizing to elongation from the primer (see, e.g.,WO 93/22456).

[0276] Gene Chips.

[0277] Allelic variants can also be identified by hybridization tonucleic acids immobilized on solid supports (gene chips), as described,for example, in WO 95/11995 and U.S. Pat. No. 5,143,854, both of whichare incorporated herein by reference. WO 95/11995 describes subarraysthat are optimized for detection of a characterized variant allele. Sucha subarray contains probes designed to be complementary to a secondreference sequence, which is an allelic variant of the first referencesequence.

[0278] The present method is illustrated by the following examples,which are not intended to be limiting in any way.

EXAMPLES Materials and Methods

[0279] The following Materials and Methods were used in the workdescribed in Examples 1-5.

[0280] Sequence Alignment of FATP Clones.

[0281] The DNA sequence for mouse FATP1 was obtained from the NationalCenter for Biotechnology Information nonredundant database. cDNAs formmFATP2, 3, 4, and 5 were obtained by screening mouse expressionlibraries (purchased from GIBCO/BRL, Rockville, Md.) with probes derivedfrom the cloned expressed sequence tags (ESTs) (Research Genetics,Huntsville, Ala.). Full-length clones were obtained for mmFATP2 and 5and partial sequences for mmFATP3 and 4. The sequences described hereinhave been deposited in the GenBank database (Accession Nos. FATP2,AF072760; FATP3, AF072759; FATP4, AF072758; FATP5, AF072757).

[0282] Neither FATP2 nor FATP5 contains an in-frame stop codon upstreamof the putative initiator methionine; initiator methionines wereassigned by homology with that in mmFATP 1 and by the presence of asignal sequence immediately after it. The Mycobacterium tuberculosis,Caenorhabditis elegans, and Saccharomyces cerevisiae sequences werepresent in the dbEST database as part of the sequencing projects forthese organisms. Sequences were aligned utilizing a ClustalX algorithmand the resulting alignment exported to SeqVu. Homologous amino acidsubstitutions are boxed in FIG. 1 and were determined using the Dayhoff250 method with a 50% homology cutoff.

[0283] Cell Transfection and LCFA Uptake.

[0284] COS cells were cotransfected using the DEAE-dextran method withthe mammalian expression vector pCDNA 3.1 (Invitrogen, Carlsbad, Calif.)expressing the gene for CD2 (pCDNA-CD2) in combination with either apCDNA 3.1 or pCMVSPORT2 (GIBCO/BRL, Rockville, Md.) expression vectorcontaining one of the murine or nematode FATP genes (pCDNA-mmFATP1,pCDNA-FATP2, pCMVSPORT-FATP5, pCDNA-ceFATPb). Two days aftertransfection, cells were assayed for CD2 expression with aphycoerythrin-coupled anti-CD2(PE-CD2) monoclonal antibody (PharMingen,Franklin Lakes, N.J.), and fatty acid uptake was assayed with aBODIPY-labeled fatty acid analogue (Molecular Probes). Briefly, cellswere washed twice with PBS (phosphate buffered saline) and stained withPE-CD2 at 4° C. for 30 min in PBS containing 10% fetal calf serum. Theywere then washed three times with PBS/fetal calf serum for 5 minfollowed by an incubation for 2 min at 37° C. in fatty acid uptakesolution, which contained 0.1 μM BODIPY-FA and 0.1% fatty acid-free BSA(bovine serum albumin) in PBS (Schaffer, J. E. & Lodish, H. F. (1994)Cell 79:427-436). After 2 min, the cells were washed four times withice-cold PBS/0.1% BSA. The cells were then removed from the plates withPBS containing 5 mM EDTA and resuspended in PBS containing 10% fetalcalf serum and 10 mM EDTA. PE-CD2 and BODIPY-FA fluorescence weremeasured using a FACScan (Becton Dickinson, Franklin Lakes, N.J.). COScells were gated on forward scatter (FSC) and side scatter (SS). Cellsexhibiting more than 300 CD2 fluorescence units (dsim) representing 15%of all cells were deemed CD2 positive and their BODIPY-FA fluorescencewas quantitated.

[0285]E. coli-Based LCFA Uptake Assay.

[0286] The full-length coding region of mtFATP and a control protein,the mammalian transcription factor TFE3, were subcloned into theinducible, prokaryotic expression vector pET (Novagen, Madison, Wis.).Expression was induced with 1 mM isopropyl β-D-thiogalactoside (IPTG)for 1 hour, or cells were left uninduced. Cells were washed in PBS/0.1%BSA and resuspended in 1 ml PBS/0. 1% BSA containing 0.1 μM[³H]palmitate (NEN) at 37° C. Uptake was stopped after the indicatedincubation time by transferring the cells onto filter paper using a cellharvester (Brandel, Bethesda, Md.). Filters were washed extensively withice-cold PBS/0.1% BSA, and [³H]palmitate was quantitated byscintillation counting.

[0287] Northern Blots.

[0288] Northern blot analysis of murine FATP expression was done usingpoly(A) mRNA blots (Clontech, Palo Alto, Calif.). Probes of each of theFATPs were derived from the 3′ untranslated regions of each gene andwere <60% identical in sequence. Probes were labeled by random priming(Boehringer Mannheim, Indianapolis, Ind.) and hybridized at 65° C. Blotswere extensively washed in 0.2% SSC/0.1% SDS at 65° C.

[0289] Generation of Phylogenetic Trees.

[0290] Complete and partial sequences for FATP genes from human, rat,mouse, puffer fish, Drosophila melanogaster, C. elegans, S. cerevisiae,and M. tuberculosis were aligned using ClustalX. A homologous region of48 amino acids (residues 472-519 in mmFATP1) from all of the genes wasused to determine phylogenetic relationship within ClustalX. Based onthese data a phylogenetic tree was generated using Tree View PPC (FIG.5).

[0291] Nomenclature.

[0292] It is proposed that the FATP genes be given a species specificprefix (mm, Mus musculus; hs, Homo sapiens; mt, M tuberculosis; dm, D.melanogaster; ce, C. elegans, sc, S. cerevisiae) and numbered such thatmammalian homologues in different species share the same number butdiffer in their prefix. Since the two C. elegans genes cannot be pairedwith a specific human or mouse FATP, they have been designated ceFATPaand ceFATPb.

Example 1 Identification of Novel Mammalian FATPs

[0293] The National Center for Biotechnology Information EST databasewas screened, using the mouse FATP protein sequence (mmFATP1), toidentify novel FATPs. This strategy led to the identification of morethan 50 murine EST sequences which could be assembled into five distinctcontiguous DNA sequences (contigs). One contig was identical to thepreviously cloned FATP, which has been renamed FATP1. Another, which hasbeen renamed FATP2, is the murine homologue of a rat gene previouslyidentified by others as a very long chain acyl-CoA synthase (Uchiyama,A., Aoyama, T., Kamijo, K., Uchida, Y., Kondo, N., Orii, T. & Hashimoto,T. (1996) J. Biol. Chem. 271:30360-30365). The other three contigsrepresented novel genes (FATP3, 4, and 5). Full-length clones for FATP2and FATP5 and nearly complete sequences for FATP3 and 4 (FIG. 1) wereobtained by screening cDNA libraries made from mouse day 10.5 embryosand adult liver. Also identified were human homologues for each of themurine genes in the EST database. A sixth human gene was alsoidentified; whether this gene is also present in the mouse will requireadditional studies. Map positions are given in Tables 2 and 3.

[0294] The genetic loci for all of the human genes, with the exceptionof FATP5 which was already mapped as an unknown EST, were determinedusing the radiation hybrid panels. The map positions given below showthe distance (in centiRays) from the closest framework marker. As aguideline, there are approximately 300 kb/cR. TABLE 2 Mapping Data forHuman Genes hsFATP1 Chromosome Chr19 places 13.35 cR from WI-6344 (lod >3.0) hsFATP2 Chromosome Chr15 places 4.92 cR from D15S126 (lod > 3.0)hsFATP3 Chromosome Chr1 places 13.24 cR from WI-2862 (lod > 3.0) hsFATP4Chromosome Chr9 places 7.80 cR from WI-9685 (lod > 3.0) hsFATP5 unknownEST previously mapped to near D19S418 hsFATP6 Chromosome Chr5 places1.41 cR from WI-4907 (lod > 3.0)

[0295] The mouse map is an internal backcross panel consisting of 188mouse backcross DNA's plus 4 controls (B6, Spretus, F1, Water). Thebackcross was constructed by crossing B6 by Spretus animals and thencrossing those F1's back to B6. Mapping is accomplished by takingadvantage of recombinational events during meiosis, and the use of PCRprimers to detect the differences (by size or re-annealing events) atany given locus between the B6 and Spretus allele.

[0296] For the purposes of mapping, a novel set of primers (gene ofinterest) is used to amplify from all 188 DNA's and then typed as beinga B6 (“B”) or a Spretus (“S”). This string of B's and S's is enteredinto the Map Manager program, which does a best fit calculation bycomparing the string of 188 typings from the gene of interest to allloci already extant in the panel, for all 20 chromosomes. The gene ofinterest is then assigned to a particular area on a particularchromosome according to a number of parameters, including theminimalization of double cross-overs, and the highest LOD scores.Indicated in Table 3 are distances to the closest markers on either sideof the FATP locus. TABLE 3 Mapping Data for Mouse Genes mmFATP1Chromosome 8 places 2.82 cM from D8Mit132 (lod 43.4) and 1.81 cM fromD8Mit74 (lod 43.5) mmFATP2 Chromosome 2 places 1.29 cM from D2Mit258(lod 47.9) and 1.75 cM from D2NDS3 (lod 44.9) mmFATP3 Chromosome 3places 2.54 cM from D3Mit22 (lod 29.5) and 19.62 cM from D3Mit42 (lod13.6) mmFATP4 Chromosome 2 places 13.78 cM from D2Mit1 (lod 22.9) and3.85 cM from D2Mit65 (lod 41.9) mmFATP5 Chromosome 7 places 7.28 cMproximal of D7Mit21 (lod 28.3)

Example 2 Assessment of Function

[0297] The ability of the newly identified mouse genes to function asfatty acid transporters was assessed using a fluorescence-activated cellsorting-based assay. COS cells were transiently cotransfected withexpression vectors encoding the cell surface protein CD2 and eithermmFATP1, mmFATP2, or mmFATP5, respectively. Two days after transfection,COS cells were stained with an antibody to CD2 and then incubated with aBODIPY-labeled fatty acid [BODIPY-FA, (Schaffer, J. E. & Lodish, H. F.(1994) Cell 79:427-436)]. The cells were then washed extensively, liftedoff the dish, and analyzed by fluorescence-activated cell sorting. Asjudged by the number of CD2-positive cells, the transfection efficiencywas approximately 20-30%. Fatty acid uptake was quantitated in thetransiently transfected COS cells by measuring the BODIPY-FAfluorescence of the CD2-positive cells. Expression of CD2 had no effecton fatty acid uptake as shown by the finding that COS cells expressingonly the transfected CD2 cDNA (CD2-positive) had the same low level ofBODIPY-FA uptake as did untransfected (CD2-negative) control cells (FIG.2A, control). In COS cells cotransfected with CD2 and mmFATP1, mmFATP2,or mmFATP5, uptake of BODIPY-FA by the transfected (CD2-positive) cellswas increased between 15- to 90-fold over control (CD2 cDNA only) cells(FIGS. 2A-2D).

Example 3 Expression Patterns of Murine FATPs

[0298] Expression patterns of members of the murine FATP gene familywere characterized by Northern blot analysis; to avoidcross-hybridization, the probes used were from the 3′ untranslatedregion of these genes, which are less than 60% identical in sequence.The expression pattern of FATP1 agrees with that previously found(Schaffer, J. E. & Lodish, H. F. (1994) Cell 79:427-436). Here,expression was seen primarily in heart and kidney. FATP2 is expressedalmost exclusively in liver and kidney, which corresponds to thereported tissue distribution of the rat homologue [very long chainacyl-CoA (VLACS)] as assessed by Western blotting (Uchiyama, A., Aoyama,T., Kamijo, K., Uchida, Y., Kondo, N., Orii, T. & Hashimoto, T. (1996)J. Biol. Chem. 271:30360-30365). FATP3 is present in lung, liver, andtestis. FATP5 is expressed only in liver and cannot be detected in othertissues even when the blot is overexposed. The human homologue of FATP5is also liver specific and is not expressed in a wide array of othertissues tested, including fetal liver.

Example 4 FATPs Are Evolutionarily Conserved

[0299] The EST database was searched, using sequences conserved amongthe five murine FATP genes, for FATP genes in other organisms. Twohomologues were found in C. elegans and one in M. tuberculosis. One ofthe C. elegans genes was cloned from a cDNA library and expressed in COScells, as described for the murine FATPs. Overexpression of the nematodeFATP resulted in a 15-fold increase of BODIPY-FA uptake compared withcontrol cells (FIG. 3). The mycobacterial FATP gene was isolated from aphage library and assessed for its ability to facilitate fatty aciduptake. E. coli transformed with a prokaryotic, isopropylP-D-thiogalactoside-inducible expression vector containing themycobacterial FATP gene demonstrated a significant increase in the rateof [³H]palmitate uptake after induction, compared with uninducedbacteria or E. coli transformed with a control protein (FIG. 4). NovelFATP genes were also identified in F. rubripes (puffer fish) and D.melanogaster.

Example 5 Phylogenetic Tree of FATPs

[0300] Faergeman et al. (Faergeman, N. J., DiRusso. C. C., Elberger, A.,Knudsen, J. & Black, P. N. (1997) J. Biol. Chem. 272:8531-8538)identified three regions of very strong conservation between the scFATPand mmFATP1 genes. The sequences of the FATPS were compared over a311-amino acid FATP “signature sequence” which includes these conservedregions corresponding to amino acids 246-557 in mmFATP1 (underlined inFIG. 1). When compared with the National Center for BiotechnologyInformation nonredundant database, only one region of the “FATPsignature sequence” shows significant homology to other proteins. Thissmall stretch of amino acids (underlined in FIG. 1) is an AMP-bindingmotif found in a multitude of other proteins, such as acyl-CoA synthase,several CoA lipases, and gramicidin S synthetase component II (Schaffer,J. E. & Lodish, H. F. (1994) Cell 79:427-436). The relevance of thismotif to fatty acid transport is unclear. Other highly conserved regionsamong the FATPs, including long stretches of amino acids >90% identicalfrom mycobacteria to humans, are not found in any other class ofproteins. A 48-amino acid segment of the FATP signature sequence wasused to construct a phylogenetic tree (FIG. 5). Each of the human andmouse genes form their own branch; hsFATP6, which as yet has no murinehomologue, is most closely related to hsFATP3 and mmFATP3. As expected,mVLACS is closer in sequence to mmFATP2 than to hsFATP2. The FATP genesof invertebrates i.e., C. elegans and D. melanogaster, are most closelyrelated to each other. Surprisingly, the mycobacteral gene is moreclosely related to the human and mouse FATP5 genes than to the FATPs ofany of the lower organisms. Whether this reflects coevolution of themycobacterial and human genes awaits further study.

[0301] Materials and Methods

[0302] The following materials and methods were used in the workdescribed in Examples 6-10.

[0303] Isolation of full-length human FATP 1 and 4

[0304] Full-length clones encoding human FATP1 and human FATP4 wereidentified by searching databases for sequences similar to murineFATP1-5 coding regions using the BlastX algorithm (Altschul et al., J.Mol. Biol. 215: 403-410, 1990).

[0305] A concatamer of nucleotide sequences comprising the codingsequences of mmFATP1 (Genbank Accession U15976), mmFATP2, mmFATP3 (SEQID NO:6), mmFATP4 (SEQ ID NO:8) and mmFATP5 (SEQ ID NO:10) was used tosearch the Millennium database using the BLASTX algorithm. Sequenceswith a score >150 were evaluated for whether they represented known FATPcoding sequences.

[0306] Human clones with similarity to the 5′ end of murine FATPsequences were sequenced completely. Clones encoding full-length humanFATP1 were obtained from a heart cDNA library constructed in themammalian expression vector pMET7 (Tartaglia et al., Cell, 83:1263-1271, 1995). Clones encoding full-length human FATP4 were obtainedfrom a spleen cDNA library constructed in the mammalian expressionvector pMET7.

[0307] Isolation of Full-Length Human FATP6

[0308] Several clones encoding human FATP6 were identified by searchingpublic databases as described above. Five clones were analyzed furtherby restriction digestion and DNA sequencing. One of these clones(Genbank Accession # AA412064) appeared to be full-length and its entireinsert was sequenced.

[0309] DNA Sequence Analysis

[0310] Sequences were aligned with the DNAStar program using the Clustalmethod. Hydrophobicity plots were generated with DNA Strider using theKyte Doolittle method.

[0311] In situ Hybridization

[0312] Tissues were collected from 8 week old C57/B16 mice. Tissues werefresh frozen, cut on a cryostat at 10 μm thickness and mounted onSuperfrost Plus slides (VWR). Sections were air dried for 20 minutes andthen incubated with ice cold 4% paraformaldehyde (PFA)/phosphatebuffered saline (PBS) for 10 minutes. Slides were washed 2 times 5minutes with PBS, incubated with 0.25% acetic anhydride/1 Mtriethanolamine for 10 minutes, washed with PBS for 5 minutes anddehydrated with 70%, 80%, 95% and 100% ethanol for 1 minute each.Sections were incubated with chloroform for 5 minutes. Hybridizationswere performed with ³⁵S-radiolabeled (5×10⁷ cpm/ml) cRNA probesgenerated from the 3′ untranslated regions of mouse FATPs by PCRfollowed by in vitro transcription in the presence of 50% formamide, 10%dextran sulfate, 1× Denhardt's solution, 600 mM NaCl, 10 mM DTT, 0.25%SDS and 10 μg/ml tRNA for 18 hours at 55° C. After hybridization, slideswere washed with 10 mM Tris-HC1 pH 7.6, 500 mM NaCl, 1 mM EDTA (TNE) for10 minutes, incubated in 40 μg/ml RNase A in TNE at 37° C. for 30minutes, washed in TNE for 10 minutes, incubated once in 2× SSC at 60°C. for 1 hour, once in 0.2× SSC at 60° C. for 1 hour, once in 0.2× SSCat 65° C. for 1 hour and dehydrated with 50%, 70%, 80%, 90% and 100%ethanol. Localization of mRNA transcripts was detected by dipping slidesin Kodak NBT-2 photoemulsion and exposing for 7 days at 4° C., followedby development with Kodak Dektol developer. Slides were counter stainedwith haematoxylon and eosin and photographed. Controls for the in situhybridization experiments include the use of a sense probe which showedno signal above background in all cases.

[0313] Northern Blotting

[0314] Human mRNA blots were obtained from Invitrogen or Clontech. PCRfragments from the 3′ untranslated regions of human FATPs were used asprobes. Blots were probed with ³²P-labeled DNA probes using theRapid-Hyb buffer (Amersham, Buckinghamshire, UK) according to themanufacturer's instructions.

[0315] Cell transfection and LCFA uptake. COS cells were cotransfected,using lipofectamine (GIBCO BRL, Rockville, Md.) according to themanufacturer's instructions, with the mammalian expression vectorpCDNA3.1 (Invitrogen, Carlsbad, Calif.) expressing the gene for CD2 incombination with a pMET7 expression vector (Tartaglia et al., Cell,83:1263-1271, 1995) containing hsFATP1 (pMET7-hsFATP1) or hsFATP4(pMET7-hsFATP4) or pMET7 alone. Two days after transfection, cells wereassayed for CD2 expression with a phycoerythrin-coupled anti-CD2(PE-CD2) monoclonal antibody (PharMingen, Franklin Lakes, N.J.), andfatty acid uptake was assayed with a BODIPY-labeled fatty acid analog(Molecular Probes) as described above.

Example 6 Determination of Expression of mmFATPs

[0316] mmFATP4, and to lesser extent mmFATP2, are expressed at highlevels in the brush border layer of the small intestine.

[0317] Cell transfection and LCFA uptake. COS cells were cotransfected,using lipofectamine (GIBCO BRL, Rockville, Md.) according to themanufacturer's instructions, with the mammalian expression vectorpCDNA3.1 (Invitrogen, Carlsbad, Calif.) expressing the gene for CD2 incombination with a pMET7 expression vector (Tartaglia et al., Cell,83:1263-1271, 1995) containing hsFATP1 (pMET7-hsFATP1) or hsFATP4(pMET7-hsFATP4) or pMET7 alone. Two days after transfection, cells wereassayed for CD2 expression with a phycoerythrin-coupled anti-CD2(PE-CD2) monoclonal antibody (PharMingen, Franklin Lakes, N.J.), andfatty acid uptake was assayed with a BODIPY-labeled fatty acid analog(Molecular Probes) as described above.

[0318] Absorption of dietary fat requires transport of free fatty acidsacross the apical membrane of epithelial cells in the small intestine.Previous studies suggested that this transport is protein-mediated;however, the transport protein had not yet been identified. In situhybridization was performed on each of the three regions of the smallintestine—duodenum, jejunum and ileum—as well as the colon, using probesfrom the 3′ untranslated regions of mmFATP1, mmFATP2, mmFATP3, mmFATP4and mmFATP5, to determine whether any of the mouse FATPs are expressedin the small intestine. It was expected that a protein involved in fattyacid absorption would be expressed in the epithelial cells of the smallintestine, but absent from the colon.

[0319] Expression of mmFATPs in the jejunum was identical to that in theileum in all cases. High levels of mmFATP4 mRNA were present in theepithelial cells of the jejunum and ileum, and lower, but significant,amounts were detected in the epithelial cells of the duodenum.Significantly, FATP4 mRNA was absent from other cell types of the smallintestine and no FATP4 mRNA could be detected in any of the cells of thecolon. FATP2 mRNA was present in the epithelial cells of the duodenum ata level similar to that of FATP4, but was present at lower levels in thejejunum and ileum. No signals above background were detected formmFATP1, mmFATP3 and mmFATP5 in any of the intestinal tissues. mmFATP3and FATP5 were clearly detectable by in situ hybridization in adultliver and mmFATP1 could be detected in a variety of tissues on a wholeembryo in situ, indicating that the FATP1, 3, and 5 probes were working.

[0320] mmFATP4 expression is predominant in the small intestine comparedto the other organs of the mouse embryo. In the small intestine, FATP4expression is limited to differentiated enterocytes, while no signal isdetected in the connective tissue or the undifferentiated epithelialcells in the crypts. Differentiated enterocytes are known to be thecells that mediate the uptake of fatty acids. FATP4 is specifically andstrongly expressed in the epithelial cells of adult murine duodenum andileum but not colon. Other FATPs, such as FATP5, are not expressed inthe small intestine. Thus, FATP4 is the major FATP in the mouse smallintestine. Given its high level of expression, it is likely that FATP4,and to a lesser extent FATP2, play an important role in the absorptionof fatty acids.

[0321] mmFATP2, and mmFATP5 are Expressed in Hepatocytes

[0322] Northern analysis of mmFATP2, mmFATP3, mmFATP4 and mmFATP5 showedexpression in the liver. To determine whether these proteins are presentin hepatocytes or other cells types present in liver homogenates, insitu hybridizations were performed. mmFATP2, and mmFATP5 mRNA wasclearly present in hepatocytes, and was not concentrated in other celltypes such as endothelial cells or macrophages. No signal abovebackground was detected for mmFATP 1 in any of the cell types in theliver, consistent with the results of the Northern blotting.

Example 7 Isolation and Sequence Analysis of Full-Length Human FATP 1and Full-Length Human FATP4

[0323] To identify human cDNA clones encoding FATP family members,Millennium databases were searched for sequences similar to murineFATP1-5 coding regions. Two clones were. analyzed in detail; inspectionof the entire DNA sequence of these two clones showed that they encodethe human orthologs of mmFATP1 and mm FATP4, respectively. These twoclones were designated hsFATP1 and hsFATP4, and their DNA and predictedprotein sequences are shown in FIGS. 44A-44C and 45, and 50A-50C and 51.hsFATP1 is predicted to encode a 646 amino acid, 71 kD protein withmultiple membrane-spanning domains (FIG. 28A). HsFATP4 is predicted toencode a 643 amino acid, 72 kD protein with multiple membrane spanningdomains (See FIG. 29A). A comparison of the DNA sequences of mouse andhuman FATP1 and mouse and human FATP4 (FIGS. 30A-30B and 31A-31B) showsthat the mouse and human orthologs are 85% (FATP1) and 87% (FATP4)identical to each other within the coding sequences given in thesefigures. At the amino acid level, hsFATP1 and hsFATP4 are ˜90% identicalto their respective mouse orthologs within the coding region shown inthese figures (FIGS. 32 and 33). The sequence identities between mouseand human FATP1 and FATP4 are considerably higher than the ones observedbetween different FATP family members within one species (˜40%-60%) andare present in the N-terminal part of the protein, a region that ispoorly conserved between different FATP family members. This high degreeof sequence conservation clearly demonstrates that the newly identifiedhuman FATPs are orthologs of mouse FATP1 and FATP4 rather than novelFATP family members.

[0324] Table 4 is an identity/similarity matrix comparing the amino acidsequences of FATP1 and 4 from human and mouse. This shows that the genewhose sequence is shown in FIG. 43A is indeed human FATP4, since it is91% identical with the murine FATP4 but only 62% identical with theclosest related human FATP, which is FATP1. TABLE 4 Identity/SimilarityMatrix hsFATP4 mmFATP4 hsFATP1 mmFATP1 hsFATP4 — 93.2 72.3 72.0 mmFATP491.0 — 71.2 71.1 hsFATP1 61.9 61.0 — 92.4 mmFATP1 60.7 59.6 89.5 —

Example 8 Isolation and Sequence Analysis of Full-Length Human FATP6

[0325] A search of EST databases identified a set of overlapping humansequences that were similar to FATPs, but did not have a clear mouseortholog. One of these EST clones was found to encode a full-lengthcDNA. The entire insert of this clone was sequenced and designatedhsFATP6. The DNA and predicted protein sequences of hsFATP6 are shown inFIGS. 54A-54C and 55. HsFATP6 is predicted to encode a 619 amino acid,70 kD protein with multiple membrane-spanning domains (FIG. 35A). Acomparison of the amino acid sequences of hsFATP6 with other human FATPsshows about 37% identity to either hsFATP1 or hsFATP4 (FIG. 36). Thisdegree of sequence identity is similar to what is observed betweendifferent mouse FATPs. The phylogenetic analysis described above clearlydemonstrates that hsFATP6 is a member of the FATP family, but not anortholog of any of the mouse FATPs. Comparisons were done with “ALIGN”(E. Myers and W. Miller, “Optimal Alignments in Linear Space,” CABIOS4:11-17 (1988) using standard settings.

Example 9 Tissue Distribution of Human FATPs

[0326] The tissue distribution of human FATPs was assessed by Northernblotting. Human FATP3 was expressed in a large variety of tissues. Incontrast, human FATP5 was present at high levels in the liver, but wasundetectable in all other tissues examined. Thus, both hsFATP3 andhsFATP5 recapitulate the expression pattern of their mouse orthologs(see above). HsFATP6 is a novel FATP with no mouse ortholog as yet.Northern blotting shows that hsFATP6 is expressed at high levels in theheart, but is undetectable in other tissues, including skeletal andsmooth muscle. This tissue distribution suggests that human FATP6performs an important role in energy metabolism in the heart; blockingFATP6-mediated fatty acid transport may therefore be beneficial for anumber of heart diseases, e.g., ischemic heart disease.

[0327] To identify the major FATP expressed in the human smallintestine, Northern blotting was performed on a blot containing mRNAfrom human stomach, jejunum, ileum, colon, rectum and lung. hsFATP5 andhsFATP6 were undetectable in any of these tissues. FATP5 is onlyexpressed in liver and FATP6 only in heart. hsFATP2 was weakly expressedin the colon, and an even weaker signal was detectable in jejunum, ileumand lung lanes. hsFATP3 was expressed well in the lung, but was onlyweakly expressed in the other tissues tested. Importantly, no differencewas seen in the expression of hsFATP3 between small intestine andstomach or colon, suggesting that the expression observed is not relatedto fatty acid absorption in the small intestine. hsFATP4 was clearlyexpressed in both jejunum and ileum; expression was significantly lowerin the colon and was absent in the stomach. This expression pattern isconsistent with a major role for FATP4 in absorption of fatty acids inthe human gut.

Example 10 Expression of hsFATP1 and hsFATP4 Promotes Transport of FattyAcids

[0328] COS cells were cotransfected using lipofectamine with themammalian expression vector pCDNA-CD2 in combination with one of theFATP-containing expression vectors (pMET7-hsFATP1 or pMET7-hsFATP4) oran insertless expression vector (pMET7, control) as described inMaterials and Methods for Examples 6-10. COS cells were gated on forwardscatter and side scatter. Cells exhibiting more than 400 CD2fluorescence units representing −30% of all cells were deemedCD2-positive. The percent of CD2-positive cells exhibiting aBODIPY-fluorescence of >300 is plotted for the three different vectorstested (FIG. 37).

Example 11 Stable Expression of Human FATP4 in 293 Cells

[0329] Stable cell lines were generated as follows. A DNA fragmentcontaining the entire hsFATP4 coding sequence as well as 100 nucleotidesof 5′ and 50 nucleotides of 3′ untranslated region was inserted into thevector pIRES-neo (Clontech, Palo Alto, Calif.) using standard cloningtechniques. The resulting construct or a vector control (pIRES-neo) wastransfected into 293 cells using the lipofectamine method (Gibco BRL,Rockville, Md.) according to the manufacturer's directions. Cells thathad taken up the DNA were selected with 1 mg/ml G418 (Gibco BRL,Rockville, Md.). Single colonies were picked 1 to 2 weeks aftertransfection and grown in medium containing 0.8 mg/ml G418. Colonieswere screened for the ability to take up fatty acids by measuring uptakeof a fluorescently labeled fatty acid (BODIPY-FA). About 40 coloniestransfected with the pIRES-neo containing FATP4 and ˜20 coloniestransfected with pIRES-neo control were analyzed. All 20 of the vectorcontrol clones showed amounts of BODIFY-FA uptake similar to each otherand to untransfected 293 cells. In contrast, among the 40 FATP4transfected clones, 3 had a 5- to 10-fold increased BODIPY-FA uptakecompared to any of the vector controls, and a large number (˜20) showedan approximately two-fold increase in BODIPY-FA levels. Thisdistribution is consistent with FATP4 conferring increased fatty aciduptake in these cells. One of the cell lines with the highest amount ofBODIPY-FA uptake was selected to be used for measuring uptake oftritiated fatty acid.

[0330] The uptake of tritiated oleate over time by either FATP4expressing or control cells was assayed over time. Expression of FATP4increases the rate of fatty acid uptake by over 3-fold, demonstratingthat FATP4 is, like the other FATPs, a functional fatty acid transporter(FIG. 38).

Example 12 Immuno-Staining with FATP4-Specific Antiserum

[0331] A polyclonal antiserum against the C-terminus of mmFATP4 wasraised using a GST-fusion protein having mmFATP4-specific amino acidsequence 552-643 (AVASP . . . GEEKL). In western blot experiments, thepurified antibody reacted strongly with a synthetic peptide matching theC-terminus of mmFATP4, but not with a corresponding region of mmFATP2,mmFATP3, or mmFATP5. The mmFATP4 specific polyclonal antiserum detects,in western blot experiments with enterocyte lysates from 3 differentmice, a ˜70 kDa protein, which is in accordance with mmFATP4's predictedmolecular weight of 72 kDa. The binding is specific for mmFATP4, sinceit can be completely abolished by preincubation of the antiserum withthe GST-fusion peptide used to raise the antibody.

[0332] Immunofluorescence experiments were performed using theanti-mmFATP4 antiserum on fresh frozen sections of murine smallintestine. The antibody binding demonstrates strong expression ofmmFATP4 in enterocytes, confirming the results of the in situhybridization experiments. At higher magnifications it is apparent thatmmFATP4 is expressed at the apical side of the enterocyte, indicatingthat the transporter is present in the brush border membrane, which isknown to mediate the uptake of fatty acids from the intestinal lumen.

[0333] Immuno-electron microscopy studies were performed on fresh frozenmurine intestinal cells. The gold particles used, appearing as blackspecks on the electron micrographs, indicate the subcellularlocalization of mmFATP4 to be on the microvilli of the enterocyte. Itcan be seen from electron micrographs that mmFATP4 is localizedexclusively in membranes, preferentially the apical plasma membrane,confirming that it is indeed a membrane protein.

[0334] Methods for Immunofluorescence and Immunogold Electron Microscopy

[0335] Unfixed mouse small intestine was washed with Hank's bufferedsalt solution containing 1 mM EDTA, infused with 2.3 M sucrose solution,and embedded in O.C.T., 4583 compound. The material was thick sectioned(15 μM -40 μM). The sections were washed in PBS containing 1% BSA and0.075% glycine to block non-specific binding. Primary and secondaryantibodies were diluted in PBS with 10% FCS and incubated for 1 h. Thesections were mounted in 90% glycerol/PBS containing 1 mg/mlparaphenylinediamine, and examined with a Bio-Rad MRC 600 confocal,mounted on a Zeiss Axioscop.

[0336] For the immunogold labeling, the tissue was fixed with 2%paraformaldehyde in PBS for 10 minutes, after which it was cryoprotectedby infiltration with 2.3 M sucrose in 0.1 M phosphate buffer (pH 7.4)containing 20% polyvinylpyrrolidone, and then mounted on aluminum cryonails and frozen in liquid nitrogen (Tokuyasu, K. T., J. Microscop.143:139-149, 1986). Ultrathin sections were collected oncarbon/formvar-coated nickel grids. The primary antibody (anti-FATP4)was diluted in 10% FCS in PBS and incubated overnight at 4° C., followedby donkey anti-rabbit IgG-gold (12 nm) (Jackson Labs) for 1 h. Thesections were stained in 2% neutral uranyl acetate (20 minutes) andabsorption stained with 2% uranyl acetate in 0.2% methylcellulosecontaining 3.2% polyvinyl alcohol. The sections were examined with aPhilips EM 410 electron microscope.

Example 13 Inhibition of Fatty Acid Uptake Specific to FATP4Demonstrated in Isolated Mouse Enterocytes

[0337] Phosphorothioate derivatives of the following oligonucleotideswere synthesized: FATP4-AS2 CCCCCACCAGAGAGGCTCC (SEQ ID NO:103)FATP4-AS2MM CCACCCCCGGAAAGCCTGC (SEQ ID NO:104) FATP4-S2GGAGCCTCTCTGGTGGGGG (SEQ ID NO:105)

[0338] FATP4 AS2 is the antisense oligo; it is designed to becomplementary to the sequence extending from nucleotide 10 to nucleotide28 of the mouse FATP4 coding sequence. FATP4-AS2MM is a control oligo;in the oligo every third nucleotide was changed creating mismatches; theoverall nucleotide composition is identical to FATP4-AS2 (same number ofG, A, T, C). FATP4-S2 is the sense control.

[0339] Enterocytes were isolated from the small intestine of mice andincubated for 48 h in tissue culture (FIG. 40) either withoutoligonucleotides (squares) or with 100 μM FATP4 specific sense (circles)or antisense (diamonds) oligonucleotides. The uptake over time of 25 μMoleate was then measured. While the FATP4 sense oligonucleotide did notsignificantly influence the uptake, the antisense oligonucleotideinhibited fatty acid uptake by ˜50%.

[0340] The effect of either FATP4 sense, antisense or mismatch sequenceoligonucleotides on the uptake of fatty acids was measured inenterocytes. Isolated enterocytes were incubated with increasingconcentrations of FATP4 antisense oligonucleotides (solid bars in FIG.41), or a mismatch control oligonucleotide with identical nucleotidecomposition (stippled bars), or with 100 μM of the FATP4sense-oligonucleotide (lined bar). The medium for this incubation wasDulbecco's modified Eagle's medium with 4.5 g/L glucose, I mM sodiumpyruvate, 0.01 mg/ml human transferrin and 10% fetal bovine serum. After48 hours of incubation the uptake of oleate by enterocytes was measuredover a 5 minute time interval. Measurements were done in quadruplicate.The uptake assay was done in Hank's buffered salt solution with 10 mMtaurocholate. Only the enterocytes given FATP4 antisense oligonucleotideshowed a concentration dependent decrease of fatty acid uptake,inhibiting it at a 100 μM concentration by ˜50%. This effect was FATP4specific, since only the antisense oligonucleotide which can bind to theFATP4 mRNA and block its translation inhibited uptake, but not a controloligonucleotide differing only in the sequence but not the nucleotidecontent, ruling out a toxic or otherwise nonspecific inhibitory effectof this oligonucleotide due to its chemical composition.

[0341] As a further control experiment, the uptake of oleate wasmeasured along with the uptake of methionine in the same culturedenterocytes. Antisense oligonucleotide, mismatch sequenceoligonucleotide, or no oligonucleotide was added to a concentration of100 μM to cultures of enterocytes. After incubation for 48 hours, theuptake of both ³H-labeled oleate and ³⁵S-labeled methionine was assayed.Results are shown in FIG. 42. Fatty acid uptake is at the left side ofthe paired bars; methionine uptake is on the right side of the pairedbars. The fact that amino acid uptake was not influenced by theantisense oligonucleotide treatment further supports the conclusion thatthe antisense oligonucleotide causes a specific reduction in translationof FATP4-specific mRNA.

Example 14 mmFATP2 is Expressed in Proximal Renal Tubule Epithelium

[0342] Northern analysis showed that mmFATP1, mmFATP2, and mmFATP4 arepresent in the kidney. In situ hybridization (methods as for Example 6)was performed to determine which cell type(s) of the kidney these mRNAsare expressed in. mmFATP1 mRNA was present in virtually all cellsthroughout the kidney with no obvious preference for a particular celltype. In contrast, mmFATP2 was expressed only in the renal cortex.Within the cortex, expression of mmFATP2 was restricted to theepithelial cells of the proximal renal tubules. The primary function ofproximal renal tubule cells is the reabsorption of filtered salts andnutrients (e.g., glucose), a process that requires mitochondrialoxidation and that can utilize fatty acids as energy substrates. Basedon the localization of mmFATP2, it is possible that mmFATP2 is importantfor reabsorption in the kidney by allowing uptake of an energy source(fatty acids) from the blood into renal epithelial cells. Alternatively,if fatty acids need to be reabsorbed in the kidney, similarly toglucose, FATP2 could be involved in the reabsorption of fatty acids.Determination of the subcellular localization of FATP2 will distinguishbetween these two possibilities. TABLE 5 Mouse FATP mRNA ExpressionMouse Probes mFATP1 mFATP2 mFATP3 mFATP4 mFATP5 E18.5 embryo everywhere,liver — Brain, small Mouse Probes expression brain = thymus>(hepatocytes) intestine, heart> brown superior fat, others cervicalganglion (SCG), dorsal root ganglion (DRG), other regions have lowerexpression Duodenum — villi (surface — villi (surface epithelium)epithelium) Jejunum — villi (surface — villi (surface epithelium)epithelium) Ileum — villi (surface — villi (surface epithelium)epithelium) Colon low expression very low level — in the crypt in thecrypt Kidney cortex and proximal — medulla tubules Liver — hepatocyteshepatocytes — hepatocytes Pancreas exocrine exocrine — — — secretoryunits secretory units or acinar cells; or acinar cells; endocrineendocrine pancreas (islet) pancreas (islet) are negative are negativeBrain Neuronal — — Neuronal — expression expression throughout thethroughout the brain including brain including hypothalamus hypothalamusHeart myocytes — — Testis seminiferous — seminiferous tubules tubulesLung bronchiole — — Adipose adipocyte adipocyte —

Example 15 Isolation of Full-Length Human FATP3

[0343] Full-length clones encoding human FATP3 were identified bysearching databases for sequences similar to the murine FATP 1-5 codingregions using the BlastX algorithm (Altschul et al., J. Mol. Biol. 215:403-410, 1990). Human clones with similarity to the 5′ end of murineFATP sequences were sequenced completely. A clone encoding full-lengthhuman FATP3 was obtained from a human bone library constructed in themammalian expression vector pMET7 (Tartaglia, L. A. et al., Cell 83:1263-1271, 1995). To identify human cDNA clones encoding FATP familymembers, databases were searched for sequences similar to murine FATP1-5coding regions. One clone was found to encode the human ortholog ofmmFATP3 and was designated hsFATP3. The DNA and predicted proteinsequences of hsFATP3 are shown in FIGS. 94A and 94B. hsFATP3 ispredicted to encode a 702 amino acid 75.6 kD protein with multiplemembrane-spanning domains. A comparison of the DNA sequences of mouseand human FATP3 shows that the mouse and human orthologs are 81%identical to each other within the coding region. At the amino acidlevel, hsFATP3 is ˜86% identical to mm FATP3 within the coding region.The sequence identities between mouse and human FATP3 are considerablyhigher than those observed between different FATP family members withinone species (˜40%) and are present in the N-terminal part of theprotein, a region that is poorly conserved between different FATP familymembers.

Example 16 Substrate Specificity of Fatty Acid Transport inhsFATP-Transfected Clones

[0344] Using a mammalian expression vector, we generated 40 stable 239cell lines expressing hsFATP4 and 20 cell lines transfected with acontrol plasmid. The ability of the different cell lines to take up FA,as assessed by uptake assays using the fluorescently labeledBodipy-palmitate, correlated well with their FATP4 expression levelsdetermined by Western blotting (FIG. 95). All 20 vector control clonesshowed amounts of Bodipy-FA uptake similar to each other and tountransfected 239 cells. In contrast, among the 40 FATP4 transfectedclones, a large number (˜20) showed an approximately 2-fold increase inBodipy-FA uptake compared to any of the vector controls, and three had a5- to 10-fold increase in Bodipy-FA uptake.

[0345] Several of the cell lines with the highest amount of Bodipy-FAuptake as well as isolated primary enterocytes were used to measure theuptake of radiolabeled FAs. Short-term uptake by 293 cells andenterocytes of all FAs tested was linear (FIG. 97). hsFATP4 expressionenhanced the rate of palmitate uptake approximately 3 fold over 293cells transfected with vector alone (FIG. 97) and also accelerated theuptake of oleate but not of linolate, arachidonate, octanoate, butyrateor cholesterol (Table 6). Isolated primary enterocytes showed a similarpreference for palmitate and oleate, and absence of transport ofarachidonate, octanoate, and butyrate, but displayed a more robusttransport of linolate and cholesterol than the transfected 293 cells.

[0346] To further characterize the substrate specificity of FATP4, wemeasured the uptake by stably transfected 293 cells of 5 μM Bodipy-FA inthe presence of a 20 fold molar excess (i.e., 100 μM) of FAs,FA-derivatives and lipid soluble vitamins and hormones. Both saturatedand non-saturated fatty acids containing 10 to 26 C atoms stronglycompeted for uptake of Bodipy-palmitate (FIG. 96 and Table 7) and thusare presumed to be substrates of FATP4. In contrast, fatty acids witheight or fewer C atoms did not compete and thus are presumed not to beFATP4 substrates. Similarly, esters of long chain FAs and otherhydrophobic molecules tested had no effect on uptake ofBodipy-palmitate.

[0347] LCFA Uptake Assays (Methods)

[0348] Bodipy-FA uptake assays using FACS were performed, adapted to a96-well format. LCFA uptake assays with enterocytes or with stablytransfected 293 cells were done as follows. Mixed micelles ofradiolabeled FA (NEN) and taurocholate (Sigma) in HBS were generated bybrief sonication at 37° C. Equal volumes of cells and micelle solutionwere mixed, resulting in a final FA concentration of 25 μM for antisenseassays and 10 μM for substrate specificity assays. Final taurocholateconcentration was 5 mM. Cells were incubated for the indicated amount oftime at 37° C. The assay was stopped by transferring the cells ontofilter paper followed by extensive washes with ice-cold HBS containing0.1% BSA using a cell harvester (Brandell). Incorporated oleate was thendetermined by β-scintillation counting (Beckman). TABLE 6 Uptake ofDifferent Substrates by FATP4 Expressing Cell Lines and Enterocytes 293Cells Stably 293 Cells Expressing FATP4 Fatty Acid Control* FATP4specific Enterocytes* Palmitate 564 1695 1131 3036 Oleate 662 1122 459117 Linolate 640 673 33 116 Arachidonate 3 5 2 0 Octanoate 0 0 0 5Butyrate 0 50 50 73 Cholesterol 319 345 26 531

[0349] TABLE 7 Competition of Bodipy-FA Uptake by FATP4 Expressing CellsFatty Acids Formula Competition Butyric Acid C₄H₈O₂ − Caproic AcidC₆H₁₂O₂ − Caprylic Acid C₈H₁₆O₂ − Capric Acid C₁₀H₂₀O₂ ++ Lauric AcidC₁₂H₂₄O₂ ++ Myristic Acid C₁₄H₂₈O₂ ++ Palmitic Acid C₁₆H₃₂O₂ ++ StearicAcid C₁₈H₃₆O₂ + Oleic Acid C₁₈H₃₄O₂ ++ Linoleic Acid C₁₈H₃₂O₂ ++Arachidic Acid C₂₀H₄₀O₂ ++ Lignoceric Acid C₂₄H₄₈O₂ ++ Cerotic AcidC₂₆H₅₂O₂ ++ Fatty Acid Derivatives Palmitic Acid Methyl C₁₇H₃₄O₂ − EsterStearic Acid Methyl Ester C₁₉H₃₈O₂ − Oleic Acid Ethyl Ester C₂₀H₃₈O₂ −Oleic Acid Oley Ester C₃₆H₆₈O₂ − Oleoyl CoA C₃₉H₆₈N₇O₁₇P₃S − CholesterylOleate C₄₅H₇₈O₂ − Lipid-Soluble Vitamins & Hormones Retinoic Acid(Pro-Vitamin A) C₂₀H₂₈O₂ ± Ergocalciferol (Vitamin D2) C₂₈H₄₄O₂ −Tocopherol (Vitamin E) C₂₉H₅₀O₂ − 3-Phytylamenadione (Vitamin C₃₁H₄₆O₂ −K1) Prostaglandin E2 C₂₀H₃₂O₅ −

Example 17 Identification and Characterization of the FATP5 Promoter

[0350] Methods

[0351] BAC Isolation and Luciferase Constructs

[0352] An arrayed BAC library was screened by PCR for FATP5 genomicclones. PCR primers designed by a program from the Whitehead Institute'sGenome Center specifically amplified a single band of the correct sizefrom mouse genomic DNA. Two putative BACs containing the FATP5 genomicsequence were identified and the presence of FATP5 sequence wasconfirmed by dot hybridization of the BAC with the mmFATP5 cDNA.

[0353] After isolation of positive BACs, large amounts of bacteria weregrown and DNA prepared using a Qiagen maxi-prep kit (Qiagen, Venlo, TheNetherlands). The BAC was digested with Sac I and ligated into pZero-2(Invitrogen, Carlsbad, Calif.). Inserts containing mmFATP5 genomicsequence were identified by screening colony lifts of the ligation withan β-³²P-ATP radiolabeled, random primed (Boehringer-Mannheim,Indianapolis, Ind.) mmFATP5 cDNA as a probe. Positive colonies werepicked and restriction analysis with Sac I revealed them to contain anidentical, large insert of 8-10 kb. Digestion of the Sac I fragment withBstX I yielded three pieces that were subsequently subcloned into pZeroand sequenced using an ABI sequencer (Research Genetics). A 1.3 kb piececontaining sequence immediately upstream of the FATP5 initiatormethionine was subcloned into the Xho I and Bgl II sites of thepromoter-less pGL3 luciferase reporter vector (Promega Corp., Madison,Wis.). 7 kb of additional upstream sequence was subcloned into the Xho Iand Sac I sites of the prior construct to yield a final constructcontaining approximately 8 kb of genomic sequence upstream of theinitiator methionine. Deletions of the FATP5 promoter were constructedusing PCR with the 1.3 promoter construct as the template. Products wereamplified with primers containing Hind III (5′ primer) and Xho 1 (3′primer) sites using Elongase (Gibco, Rockville, Md.). The resultingfragments were cut with Hind III and Xho I and subcloned into thecorresponding sites of the promoter-less pGL3 luciferase reportervector. The internal 30 base pair deletions, GC box mutations, and 10nucleotide linker scan were all created with the Quickchange mutagenesiskit (Stratagene, La Jolla, Calif.) according to the manufacturer'sinstructions. At least two different bacterial colonies were picked foreach construct. The inserts from both colonies were sequenced to checkfor unintended point mutations and both constructs were assayed forluciferase activity.

[0354] Cell Culture, Transfection, and Luciferase Measurements

[0355] HepG2, Hep3B, HT1080, 3T3-L1, BOSC, and HACAT cells were grown inDMEM supplemented with 10% fetal calf serum, 1× penicillin-streptomycinand glutamine (Gibco, Rockville, Md.). Mink lung cells were grown in MEMsupplemented with 10% fetal calf serum, 1× minimal essential aminoacids, 1× penicillin-streptomycin and glutamine. The evening prior totransfection, cells were plated at 50-60% confluence in 24 well dishes.The following morning, cells were placed in 2 mls of fresh media and 250μL of a CaPO₄ solution (Invitrogen, Carlsbad, Calif.) containing 2 μg ofa luciferase reporter construct and 0.5 μg of pCMV-p-gal was added tothe cells. pCMV-β-gal constitutively expresses β-galactosidase and wasused to normalize transfection efficiency (Hua et al., 1998). After 12hours, the cells were washed twice with DMEM and placed in fresh media.Thirty six hours later, the media over the cells was removed and 250 μLof 1× reporter lysis buffer (Promega Corp., Madison, Wis.) was added.After vigorous shaking for 15 minutes at room temperature, thesupernatants were transferred to Eppendorf tubes and briefly centrifugedto remove particulates. 20 μL from these tubes was used fordetermination of luciferase activity (Promega Corp., Madison, Wis.) and20 μL was used for the measurement of β-galactosidase activity(Clontech, Palo Alto, Calif.). All luciferase values were normalized toβ-galactosidase to control for transfrection efficiency and expressed asrelative luciferase units (RLU). For experiments comparing differentcell lines, promoter activity was computed as a fold induction bydividing the RLU activity of either the −8 or −271 promoter constructsby the RLU activity a promoter-less construct. Each data point was donein triplicate and each experiment was repeated a minimum of three times.

[0356] Northern Blots, Preparation of Nuclear Extracts, and Gel ShiftAssays

[0357] Human poly-A northern blots were purchased from a commercialvendor (Clontech, Palo Alto, Calif.) and probed with a piece of thehuman FATP5 3′ untranslated region specific for FATP5. Nuclear lysatesfrom HepG2 and BOSC cells were essentially prepared according to themethod of Hua et al. and stored at −80° C. (Hua et al., 1998). Probesfor gel shift assays were end labeled using T4 polynucleotide kinase(Boehringer-Mannheirn, Indianapolis, Ind.) and gel purified. Gel shiftswere performed at room temperature in 30 μL reactions comprised of 6 μL5 × binding buffer (100 mM Tris 8.0, 300 mM KCl, 5 mM EDTA, 8 mM MgCl₂,and 36% glycerol), 0.5 μL of 100 mM DTT, 1 μL of 10 mg/ml BSA, 2 μL of 2mg/ml poly dI/dC, and 5 μL nuclear lysate. Ten minutes after theaddition of nuclear lysate, 40,000 cpm of ³²P-labeled probe were added.After 20 minutes at room temperature, loading dye was added and thereaction run on a 4% non-denaturing gel.

[0358] Results

[0359] Human FATP5 mRNA is Only Expressed in Adult Liver

[0360] We had previously reported that mmFATP5 mRNA was only expressedin the liver (Hirsch et al., 1998). To determine if the human isoform ofFATP5 was also liver specific, we performed northern analysis using aprobe from the 3′ transcribed but untranslated region of the human gene.Similar to the mouse homolog, hsFATP5 is liver specific. Interestingly,hsFATP5 was not expressed in fetal liver suggesting that it may bedevelopmentally regulated.

[0361] Identification of a FATP5 Promoter

[0362] We next set out to determine the cis-acting elements responsiblefor liver specific expression of FATP5. We identified BACs containingthe FATP5 genomic locus and subcloned a 10 kb Sac I fragment which wassubsequently sequenced. The Sac I fragment contains approximately 8 kbof genomic sequence upstream of the FATP5 initiator methionine. Blastsearches using the 5′ end of the Sac I sequence revealed that itcontained coding sequence for an unknown gene immediately upstream ofFATP5. Since the FATP5 promoter is unlikely to overlap the codingsequence of another gene, we hypothesized that the 10 kb Sac I fragmentcontained the FATP5 promoter. To test this hypothesis, 8 kb of genomicDNA upstream of the translational initiator of FATP was subcloned intothe promoter-less pGL3 luciferase reporter vector. This construct wastransiently transfected into the HepG2 liver cell line and luciferaseactivity was determined. The −8 kb piece of DNA resulted in a 35 foldinduction of luciferase activity when compared to a pGL3 vector withoutthe FATP5 genomic sequence (FIG. 100). To determine if this activityreflected tissue specific transcription, the −8 kb luciferase reporterconstruct was transfected into a variety of additional cell types. Whilepromoter activity was also detected in the Hep3b hepatoma cell line,non-liver cell lines did not express luciferase above the level of thepromoter-less vector. Thus, the 8 kb upstream genomic elementrecapitulated liver specific expression in vitro.

[0363] The FATP5 Promoter Resides within the 261 Base Pairs Upstream ofthe Initiator Methionine and Requires a Single GC Box

[0364] To determine the cis-acting elements in the −8 kb of genomicsequence responsible for transcriptional activity, serial 5′ deletionsof the promoter were constructed and transfected into HepG2 cells.Surprisingly, greater than 90% of the −8 kb was dispensable for promoteractivity. A construct containing only 261 base pairs upstream of theinitiator methionine resulted in promoter activity equivalent to that ofthe −8 kb construct (FIG. 101). Identical results were obtained when thedeletion series was transfected into Hep3b cells (data not shown). Wenext determined if promoter activity of a small genetic element wastissue specific. Transfection of a construct containing 271 base pairsupstream of the initiator methionine into a variety of cell linesessentially replicated the results of the −8 kb construct in thatexpression was observed only in liver derived cell lines (FIG. 102).

[0365] Since deletion analysis revealed that bases between −261 and −218were required for promoter activity, we closely examined this region forbinding sites of known transcription factors and found the sequenceGGGGCGGGG between nucleotides −241 and −232 (FIG. 103A). This sequencebinds the Sp1 family of transcription factors and is termed a GC box. Todetermine if the activity of the −271 construct required the GC box, wemutated the GC box. The first construct deleted nucleotides −241 to −222which removed the GC box and additional downstream sequence which,although less optimal, might also bind the Sp1 family of transcriptionfactors(SEQ ID NO: 107). The second construct had three G to A pointmutations in the GC box between nucleotides −241 to −232(SEQ ID NO:108). Such mutations had previously been shown to abolishtranscriptional activity of GC boxes (Rodenburg et al., 1997). Incontrast to the wild type −271 promoter, both of the mutated constructswere transcriptionally inactive in HepG2 cells (FIG. 103B). Identicalresults were also obtained in Hep3B cells (data not shown). Thissuggests that the GC box between −241 to −232 is essential fortranscriptional activity of the FATP5 promoter. We next examined whetherthe sequences necessary for luciferase activity also bound proteins innuclear extracts from HepG2 cells. Two different oligonucleotides wereused for gel shift analysis. One oligonucleotide (AF-1) containednucleotides −250 to −230(SEQ ID NO: 111) and the other (AF-2) spannednucleotides ˜260 to ˜−200(SEQ ID NO: 109) (FIG. 104). Botholigonucleotides yielded three significant complexes from HepG2 nuclearextracts. All complexes were specific as 100 fold excess of the sameunlabeled oligonucleotide could compete for binding of the radiolabeledoligonucleotide. Mutant AF-1 oligonucleotides containing three pointmutations in the GC box did not bind any proteins in HepG2 nuclearextracts or compete for binding of nuclear proteins to the AF-1 or AF-2oligonucleotides (data not shown). Oligonucleotides AF-1 and AF-2 alsobound recombinant Spi (Promega Corp, Madison, Wis., data not shown).However, nuclear extract from BOSC cells, a kidney cell line, and HepG2cells had identical patterns of complex formation (data not shown).

[0366] Identification of Novel Sequences Required for TranscriptionalActivity of the FATP5 Promoter

[0367] While the GC box between nucleotides 241 and 232 is essential fortranscriptional activity, additional sequences downstream of the GC boxmight also be required for transcription. To determine if such sequencesexisted, we created 30 base pair internal deletions in the ˜−271construct downstream of the GC box. Constructs that had deletions insequences between 240 and 180 nucleotides upstream of the FATP5translational initiator had greatly reduced transcriptional activity inHepG2 cells (FIG. 105). To identify the specific sequences within thisregion required for FATP5 transcription, a 10 nucleotide linker(CTAACAGGAG) (SEQ ID NO: 1-13) was exchanged for wild type sequencewithin the context of the −271 base pair construct (FIG. 106).Inadvertently, the 210 to 200 construct had a single nucleotideinsertion and the 190 to 180 construct had a two nucleotide insertionrelative to the wild type sequence. However, several other linkerconstructs that also had equivalent insertions (230 to 220 or 170 to 160for example) had high levels of luciferase activity. Thus the decreasein luciferase activity in the 190 to 180 and 210 to 200 constructs isdue to changes in the nucleotide sequence and not the result of thenucleotide additions. Transfection of these DNA into HepG2 cellsrevealed two regions important for transcription. Mutating sequencesbetween nucleotides −210 and ˜−200 or between nucleotides −190 and −180drastically reduced luciferase activity (FIG. 106).

[0368] In both humans and mice, FATP5 is only expressed in the liver. Todetermine the promoter elements mediating liver specific transcription,we isolated a BAC encoding the mouse FATP5 genomic locus and sequenced10 kb upstream of the transcriptional start. Since this 10 kb of genomicDNA did not contain either a TATA box or GC rich regions found inTATA-less promoters, FATP5 may utilize non-canonical sequences fortranscription initiation. Unfortunately, attempts to identify thetranscriptional start using primer extension were unsuccessful, perhapsdue to secondary structure in the 5′ UTR. Since we did not unambiguouslydetermine the transcriptional start site, the nucleotide numbering inall of the promoter constructs refers to the distance from thetranslational start codon.

[0369] GC Box and Sp1 Transcription Factors

[0370] Since another gene was situated approximately 8 kb upstream ofthe FATP5 initiator methionine, we hypothesized that promoter elementswere likely within this region of DNA. A luciferase reporter constructcontaining this sequence was transcriptionally active in two liver celllines but was inactive in cell lines derived from lung, muscle, kidney,skin, or fibroblasts. Deletion analysis of the −8 kb reporter constructrevealed that the FATP5 promoter was contained within the 261nucleotides upstream of the initiator methionine. Promoter activity inthis −261 base pair piece required the presence of a single GC box. Gelshift assays with oligonucleotides containing this GC box revealed thepresence of three distinct complexes that required a functional GC boxfor binding. GC boxes bind the Sp1 family of transcription factors andthe multiple complexes could reflect the binding of different members ofthe Sp1 protein family or different post-translational modifications ofSp1 in HepG2 cells (Rodenburg et al., 1997). Although the Sp1 family oftranscription factors is widely expressed, Sp1 has been shown to beimportant for the transcription of several liver specific genes and isupregulated in liver after birth (Rodenburg et al., 1997). In somecases, Sp1 will facilitate the binding of a tissue specifictranscription factor to DNA. For example, Sp1 binding to DNA enhancesthe binding of C/EBPβ to an adjacent site in the liver specific CYP2D5promoter (Lee et al., 1994). Since the C/EBPβ binding site in the CYP2D5promoter is suboptimal, C/EBPβ binding to this site requires thepresence of Sp 1 or nuclear extract. A similar situation could occur inthe FATP5 promoter. Although mutations in the 10 nucleotides downstreamof the GC box had no effect on luciferase activity, we did not testmutations immediately upstream of the GC box for effects on promoteractivity. It is also possible that Sp1 might bind an unknown liverspecific transcription factor and recruit it to the FATP5 promoter.Although, there is no experimental evidence for this, Sp1 has recentlybeen shown to bind to a transcriptional activator so additionalinteracting proteins are possible (Ryu et al., 1999). Other liverspecific transcription factors

[0371] Alternatively, since the Sp1 gene family is important for thetranscription of many genes which are not liver specific, liver specificpromoter elements in the FATP5 promoter might be located elsewhere(Boisclair et al., 1993; Rongnoparut et al., 1991; Sorensen andWintersberger, 1999). Analysis of the sequence downstream of the GC boxusing TFSearch (http://pdap1.trc.rwcp.orjp/research/db/TFSEARCH.html)did not reveal any additional transcription factor binding sites ofrelevance (Heinemeyer et al., 1999; Heinemeyer et al., 1998). Further,we were unable to visually identify binding sites for known liverspecific transcription factors in this sequence (De Simone and Cortese,1992; Hanson and Reshef, 1997; Lai, 1992). Thus, we lookedexperimentally for additional promoter elements by mutating the sequencedownstream of the GC box and identified two additional sites downstreamof the GC box that were essential for FATP5 transcription. The sequencesof these sites do not conform to any known transcription factor bindingsites suggesting the either novel proteins bind these elements or thatthese elements bind known proteins in a novel manner. Preliminary gelshift data using oligonucleotides spanning these site suggests thatthese two elements may comprise a binding site for a single complex.Further additional data suggests that the complex which binds to thesetwo sites interacts with the GC box 30 base pairs upstream.Interestingly, we noted a palindromic sequence equally split betweenthese two sites (FIG. 107). Since many transcription factors bindpalindromic DNA elements, it is intriguing to speculate that these twosequences contribute to the binding site for a novel transcriptionfactor. Current investigations are focused on identifying the proteinsbinding to these novel elements and how this element interacts with theGC box.

[0372] Several studies have shown that the FATP gene family is regulatedby a variety of substances including LPS, cytokines, insulin, and diet(Frohnert et al., 1999; Hui et al., 1998; Memon et al., 1999).Especially intriguing has been a recent report that FATP1 is upregulatedby PPARα ligands in liver cell lines (Martin et al., 1997; Motojima etal., 1998). Since fatty acids may be endogenous activators of PPAR's,transcriptional regulation of FATP1 by PPAR's may represent aphysiologic feedback loop (Gottlicher et al., 1992; Grimaldi et al.,1999; Schoonjans et al., 1996). Given that liver also expresses FATP5,it will be interesting to see whether this genes is also regulated byPPARα and the tools developed here should help address this question.

[0373] Several factors make the FATP5 promoter amenable to furtherstudy. First, liver specific transcription of FATP5 can be recapitulatedusing immortalized cell lines in vitro. Second, the minimal requiredpromoter element that confers liver specific transcription is verysmall. Third, transcriptional activity of this promoter is very robust.Thus, further study of the FATP5 promoter may provide additional insightinto the mechanisms of liver specific transcription and regulation ofthe FATP gene family.

Example 18

[0374] Materials and Methods

[0375] Polyclonal antibodies were raised against proteins containing theN-terminal domain of mouse FATP2 or the C-terminal domain of mouse FATP5fused to glutathione-S-transferase (GS). Tissues for immunofluorescencewere collected from 8 week old mice and a 2 year old chimpanzee. Tissueswere fresh frozen, cut on a cryostat and mounted on slides.Immunofluorescence was performed as previously described (Stahl et al.,1999). Pictures were taken on a Zeiss confocal microscope.

[0376] To determine FATP2 expression in the gall bladder, mouse gallbladder was incubated with anti-FATP2 antibody as the primary antibodyand rhodamine-labeled anti-rabbit IG as the secondary antibody. FATP2antibody clearly stained the gall bladder epithelium, but did not resultin significant staining of other cell types. (FIG. 108)

[0377] To further study FATP2 expression, chimpanzee liver was costainedwith anti-FATP2 antibody(green) and anti CD31 antibody(red). CD31 isexpressed on endothelial cells and is used as a marker for bloodvessels. FATP2 immunoreactivity was present in large patches whichoverlap with CD31 positive areas, suggesting that FATP2 protein waspresent in the space of Diss, the area where hepatocytes exchangenutrients with the blood. This implicates FATP2 in the uptake of fattyacids into hepatocytes. In addition to areas which overlap with CD31immunoreactivity, FATP2 protein was also present on the cell surface ofhepatocytes in a small bead pattern. Immunoelectronmicroscopy of similarsections showed that FATP2 immunoreactivity was localized in the wallsof bile caniculi which are formed by the liver cells. (FIG. 109) Thepresence of FATP2 in bile caniculi in the liver as well as its presencein the gall bladder epithelium suggests a role for FATP2 in eitherabsorption or secretion of fatty acids into the bile. The levels of freefatty acids in the bile have been associated with the frequency of allstone formation.

[0378] To further study FATP5 expression, chimpanzee liver was costainedwith anti-FATP5 antibody(green) and anti CD31 antibody(red). CD31 isexpressed on endothelial cells and is used as a marker for bloodvessels. FATP5 immunoreactivity was present in large patches whichoverlap with CD31 positive areas, suggesting that FATP5 protein waspresent in the space of Diss, the area where hepatocytes exchangenutrients with the blood. (FIG. 110) This implicates FATP5 in the uptakeof fatty acids into hepatocytes.

Example 19 Identification and Characterization of Human FATP3 Proteins

[0379] Isolation of Additional HumanFATP3 Clones

[0380] An additional clone encoding human FATP3 was identified bysearching for sequences similar to murine or human FATP3 coding regionsusing the BlastX algorithm in a proprietary database, (Altschul, et al,J. Mol. Bio. 215: 403-410, 1990). One clone, which was identified byrandom library sequencing, is described as johni003f04 (SEQ ID NO:116)extends the open reading frame of the hsFATP3 polypeptide sequence by 30amino acids at the N-terminus when compared to previously discoveredsequences. The DNA sequence of this clone is shown in FIGS. 111A and111B, and the predicted protein sequence (SEQ ID NO: 117) is shown inFIG. 112. The open reading frame of this clone begins at the initialnucleotide and includes nucleotide 2240. The first ATG is located atnucleotide number 51, resulting in a predicted protein which includes730 amino acids. An FATP signature sequence (see Hirsch et al., PNAS,95:8625-8629, 1998) is clearly present between amino acids 331 and 640of hsFATP3. Within this signature sequence hsFATP3 is 48% identical tohsFATP1 at the amino acid level. A consensus AMP-binding motif has beenidentified (amino acid 333-334). Thus, hsFATP3 is clearly a member ofthe fatty acid family.

[0381] Functional Analysis of FATP3 Clones

[0382] SEQ ID NO: 116 is contained in the mammalian expression vectorpMET7 (Tartaglia, et a.., Cell, 83: 1263-1271, 1995). To determine ifthe protein encoded by this DNA sequence can mediate fatty acid uptake,SEQ ID NO: 116 was transfected into COS cells. Uptake of aBODIPY-labeled fatty acid was determined as described in previousexperiments (Hirsch, et al., PNAS, 95: 8625-8629, 1998). Transfectionwith SEQ ID NO: 116 resulted in a dramatic increase in fatty acid uptakewhen compared to transfection with vector control. In this experiment,CD31 served as a marker for transfected cells. Only CD31 positive cellswere considered for analysis (see Hirsch, et al., PNAS, 95: 8625-8629,1998 for details). The results (FIG. 113) demonstrate that SEQ ID NO:116 encodes a functional fatty acid transport protein.

[0383] Tissue Distribution of Human FATP3

[0384] Polyclonal antibodies were raised by immunizing rabbits with GSTfused to the most C-terminal 89 amino acids ofmmFATP3-(RPPQALNLVQLYSHVSENLPPYARPRFLRLQESLATTETFKQQKVRMANEGFDPSVLSDPLYVLDQDIGAYLPLTPARYSALLSGDLRI) (SEQ ID NO: 120). Western blottingexperiments with murine tissue lysates using the anti-FATP3 antiserumclosely confirmed the unique expression pattern of FATP3 as judged bynorthern blot experiments. This, together with the fact that the serumreacted only weakly with lysates from cell lines expressing eitherFATP1, -2, -4 or -5, indicates that the antibody recognizespreferentially FATP3, but not other FATP family members.

[0385] FATP3 protein was detected in mouse liver, spleen, heart, kidney,testis, white adipose tissue, and most notably in the lung. FurtherFATP3 expression in the lung was examined by immunofluorescencemicroscopy. 5 to 10 μM thick fresh frozen unfixed sections of murine andchimpanzee lungs were blocked with 10% FCS/1% donkey serum/1% BSA in HBSand incubated overnight with anti-FATP3 serum in blocking solution.After washing the sections Alexa 488 conjugated donkey anti-rabbitsecondary antibodies were used to detect bound anti-FATP3 primaryantibodies and nuclei were stained TOTO3. In later experiments,chimpanzee lung was incubated with a mixture of rabbit anti-FATP3 andmouse monoclonal anti-CD31 to visualize FATP3 as well as blood vessels.Sections were imaged on a Zeiss LSM510 confocal microscope. Experimentscarried out once with mouse and three times with chimpanzee lung tissueshowed that FATP3 is present at high levels in type-II pneumocytes, acell type responsible for secretion of surfactant, a phospholipid-richfilm critical for lung function. The exact function of FAT3 in type IIpneumocytes is not yet clear. One hypothesis is that FATP3 isresponsible for supplying fatty acid substrates for the symthesis ofsurfactant.

[0386] PCR-based experiments showed that the exocrine as well asendocrine pancreas expresses FATP3. This fact was confirmed byimmunofluorescence performed as described above for the lung sections,on chimpanzee pancreas which showed FATP3 localized to the plasmamembrane of acinar cells and a punctate expression pattern on the plasmamembrane and in the cytosol of alpha and beta cells of the pancreaticislands. The identification of a fatty acid transporter in the insulinproducing cells of the pancreas has potentially broad implications forthe treatment of type II diabetes and obesity. In both diseases, fattyacid levels in the blood are elevated and, in later stages of thedisease, lead to diminished insulin secretion by the pancreas due to theinduction of apoptosis in insulin-producing beta cells (Shimabukuro, etal., PNAS, 95: 2498-2502, 1988). Blocking fatty acid uptake into thebeta cells could possibly prevent apoptosis and maintain insulinsecretion thus preventing the progression from obesity to diabetes.

Example 20 Identification of a Fatty Acid Binding Domain in FATP4

[0387] GST fusion proteins were constructed in pGEX for four regions ofhsFATP4 (SEQ ID NO: 52; FIG. 51) which were generated by PCR andverified by sequencing. The first three fusion proteins were constructedfrom regions near the N-terminal portion of the protein. SP1 (SEQ ID NO:121) contained amino acid residues 43-239 of the hsFATP4 sequence asshown in FIG. 114A. This portion of hsFATP4 contains a lipocalin domain(as shown in FIG. 117) as well as a number of residues which in hsFATP4are upstream of the lipocalin domain. SP2 (SEQ ID NO: 122) containedresidues 43-290 of the hsFATP4 sequence as shown in FIG. 114B. Thisportion of the hsFATP4 contains a lipocalin domain and an AMP bindingdomain as well as a number of residues which are upstream of thelipocalin domain. SP3 (SEQ ID NO: 123) contained amino acid residues125-290 of the hsFATP4 sequence as shown in FIG. 114C). This portion ofthe hsFATP4 contains a lipocalin domain and an AMP binding domain, butdoes not contain the upstream residues. The fourth fusion protein wasconstructed from a region at the C-terminal end of the hsFATP4polypeptide. SP5 contained amino acid residues 417-643 of hsFATP4polypeptide as show in FIG. 114D (SEQ ID NO: 124).

[0388] Proteins were expressed in E. coli and purified on glutathioneaffinity beads using standard techniques. To determine fatty acidbinding, beads were mixed with 100 μM 14C-labeled fatty acids in mixedmicelles with taurocholate (10 mM, Sigma) and incubated for 30 minutesat room temperature. The beads were subsequently washed with PBScontaining 10 mM taurocholate and radioactivity associated with beadswas assessed by scintillation counting. A fusion to the C-terminaldomain of hsFATP4 (SP5) did not show any oleate (ARC) binding comparedto GST protein alone, while 2 N-terminal fusions (SP1 and 2) boundsignificant amounts of oleate. (FIG. 116). FATTY ACID SP1 SP2 SP3 SP5GST Oleate 25772 ± 1326 16172 ± 1639 4206 ± 631 2413 ± 186 1511 ± 525

[0389] Similar results were obtained using maltose-binding proteinfusions. MBP fusion constructs were generated by digesting the pGEX-SPconstructs with EcoRI/XhoI and ligated into pMAL digested withEcoRI/SaII. MBP fusion proteins were expressed in E. coli and werepurified under non-denaturing conditions following the manufacturer'sinstructions. To determine fatty acid binding, beads were mixed with 100μM 14C-labeled fatty acids in mixed micelles with taurocholate (10 mM,Sigma) and incubated for 30 minutes at room temperature. The beads weresubsequently washed with HBS containing 10 mM taurocholate. The proteinswere subsequently eluted from the resin with maltose and the amount offatty acid binding to MBP-SP1, -2, -3, and -5 was assessed bydetermining the radioactivity associated with the elute byβ-scintillation counting.

[0390] Unlike GST fusion proteins, MBP fusion proteins are notself-dimerizing. Further, long-chain fatty acids (such as oleate andpalmitate), but not short-chain fatty acids (such as butyrate), werespecifically bound by SP1 (FIG. 117). This selective binding isconsistent with previous reports of the substrate specificity of FATP4(Stahl, et al., Mol. Cell, 4, 299-308, 1999). The identification of afatty acid binding domain in FATP4 will be useful in the development ofsmall molecules that inhibit the binding and transport of fatty acids byFATP4 and may provide useful information on the mechanism of fatty acidtransport.

[0391] Results of Fatty Acid Binding binding to FATTY ACID CompositionMBP-SP1 binding to MBP-SP5 Oleate C18H3402 3968 2800 Palmitate C16H32024588 844 Arachidonate C20H4002 1942 1147 Butyrate C4H802 142 633

[0392] These experiments demonstrate that the FATPs of the presentinvention contain domains that bind various long chain fatty acids.Thus, polypeptides containing these domains can be prepared and utilizedto assess the modulation of binding and transport function by a varietyof agents. The polypeptides with the highest binding capacities wereshown to be those containing a lipocalin domain (such as those shown inFIG. 118) with additional upstream residues, such as those associatedwith this domain in the N-terminal portion of hsFATP4. Polypeptidescontaining domains in addition to the lipocalin domain (for example,those containing an AMP binding domain) were also shown to bind fattyacids at significant levels.

[0393]FIG. 118 contains an alignment depicting the consensus sequencesfor the six human FATP, hsFATP1, hsFATP2, hsFATP3, hsFATP4, hsFATP5 andhsFATP6 polypeptides. A lipocalin domain and an AMP binding domain foreach polypeptide are both identifed and compared. A search using thelipocalin signature sequence[DENG]-X-[DENQGSTARK]-X(0,2)-[DENQARK]-[LIVFY]-{CP}-G-{C}-W-[FYWLRH-X]-[LIVMTA]conducted on a public database (www.ebi.ac.uk/interpro/), indicated thatthe lipocalin domains of hsFATP1 and hsFATP4 are identical to thelipocalin signature sequence. In addition, a search directed toidentifying sequences having at least 80% identity to the lipocalinsignature sequence identified three additional human FATPs, hsFATP3,hsFATP5 and hsFATP6.

[0394] The following is the result of comparing individual hsFATPprotein sequences with the lipocalin domain identified for hsFATP 1 andhsFATP4. The comparison was made using the BLAST Network Service at theNational Center for Biotechnology Information. (Capitalized AA agreewith the lipocalin signature sequence.) FATP6: 114 to 125 NEpDFVhVWFGL.76% similarity (SEQ ID NO: 138) AATGAGCCGGACTTCGTTCACGTGTGGTTCGGCCTCFATP5: 182 to 194 sQAVpaLcMWLGL. 53% similarity (SEQ ID NO: 139)TCCCAGGCCGTTCCAGCCCTGTGTATGTGGCTGGGGCTG FATP4: 134 to 146 ENRNEFVGLWLGM.Identity (SEQ ID NO: 129) GAGAACCGCAATGAGTTCGTGGGCCTATGGCTGGGCATG FATP3:221 to 234 IPAGPEFLwLWTGL. 69% similarity (SEQ ID NO: 140)CTCCCCGCTGGCCCAGAGTTTCTGTGGCTCTGGTTCGGGCTG FATP2: 112 to 124GNEPAYVwLWLGL. 80% similarity (SEQ ID NO: 127)GGTAACGAGCCGGCCTACGTGTGGCTGTGGCTGGGGCTG FATP1: 136 to 148 EGRPEFVGLWLGL.Identity (SEQ ID NO: 126) GAGGGCCGGCCGGAGTTCGTGGGGCTGTGGCTGGGCCTG

[0395] References

[0396] Abumrad, N., Coburn, C., and Ibrahimi, A. (1999). Membraneproteins implicated in long-chain fatty acid uptake by mammalian cells:CD36, FATP and FABPm. Biochim Biophys Acta 1441, 4-13.

[0397] Berk, P. D., Bradbury, M., Zhou, S. L., Stump, D., and Han, N. I.(1996). Characterization of membrane transport processes: lessons fromthe study of BSP, bilirubin, and fatty acid uptake. Semin Liver Dis 16,107-20.

[0398] Berk, P. D., and Stump, D. D. (1999). Mechanisms of cellularuptake of long chain free fatty acids. Mol Cell Biochem 192, 17-31.

[0399] Boisclair, Y. R., Brown, A. L., Casola, S., and Rechler, M. M.(1993). Three clustered Sp1 sites are required for efficienttranscription of the TATA-less promoter of the gene for insulin-likegrowth factor-binding protein-2 from the rat. J Biol Chem 268,24892-901.

[0400] De Simone, V., and Cortese, R. (1992). Transcription factors andliver-specific genes. Biochim Biophys Acta 1132, 119-26.

[0401] Fitscher, B. A., Elsing, C., Riedel, H. D., Gorski, J., andStremmel, W. (1996). Protein-mediated facilitated uptake processes forfatty acids, bilirubin, and other amphipathic compounds [see comments].Proc Soc Exp Biol Med 212, 15-23.

[0402] Frohnert, B. I., Hui, T. Y., and Bernlohr, D. A. (1999).Identification of a functional peroxisome proliferator-responsiveelement in the murine fatty acid transport protein gene. J Biol Chem274, 3970-7.

[0403] Glatz, J. F., Luiken, J. J., van Nieuwenhoven, F. A., and Van derVusse, G. J. (1997). Molecular mechanism of cellular uptake andintracellular translocation of fatty acids. Prostaglandins Leukot EssentFatty Acids 5 7, 3-9.

[0404] Gottlicher, M., Widmark, E., Li, Q., and Gustafsson, J. A.(1992). Fatty acids activate a chimera of the clofibric acid-activatedreceptor and the glucocorticoid receptor. Proc Natl Acad Sci U S A 89,4653-7.

[0405] Grimaldi, P. A., Teboul, L., Gaillard, D., Armengod, A. V., andAmri, E. Z. (1999). Long chain fatty acids as modulators of genetranscription in preadipose cells. Mol Cell Biochem 192, 63-8.

[0406] Hamilton, J. A. (1998). Fatty acid transport: difficult or easy?J Lipid Res 39, 467-81.

[0407] Hanson, R. W., and Reshef, L. (1997). Regulation ofphosphoenolpyruvate carboxykinase (GTP) gene expression. Annu RevBiochem 66, 581-611.

[0408] Heinemeyer, T., Chen, X., Karas, H., Kel, A. E., Kel, O. V.,Liebich, I., Meinhardt, T., Reuter, I., Schacherer, F., and Wingender,E. (1999). Expanding the TRANSFAC database towards an expert system ofregulatory molecular mechanisms. Nucleic Acids Res 27, 318-22.

[0409] Heinemeyer, T., Wingender, E., Reuter, I., Hermjakob, H., Kel, A.E., Kel, O. V., Ignatieva, E. V., Ananko, E. A., Podkolodnaya, O. A.,Kolpakov, F. A., Podkolodny, N. L., and Kolchanov, N. A. (1998).Databases on transcriptional regulation: TRANSFAC, TRRD and COMPEL.Nucleic Acids Res 26, 362-7.

[0410] Hirsch, D., Stahl, A., and Lodish, H. F. (1998). A family offatty acid transporters conserved from mycobacterium to man. Proc NatlAcad Sci U S A 95, 8625-9.

[0411] Hua, X., Liu, X., Ansari, D. O., and Lodish, H. F. (1998).Synergistic cooperation of TFE3 and smad proteins in TGF-beta-inducedtranscription of the plasminogen activator inhibitor-1 gene. Genes Dev12, 3084-95.

[0412] Hui, T. Y., Frohnert, B. I., Smith, A. J., Schaffer, J. E., andBemlohr, D. A. (1998). Characterization of the murine fatty acidtransport protein gene and its insulin response sequence. J Biol Chem273, 27420-9.

[0413] Lai, E. (1992). Regulation of hepatic gene expression anddevelopment. Semin Liver Dis 12, 246-51.

[0414] Lee, Y. H., Yano, M., Liu, S. Y., Matsunaga, E., Johnson, P. F.,and Gonzalez, F. J. (1994). A novel cis-acting element controlling therat CYP2D5 gene and requiring cooperativity between C/EBP beta and anSp1 factor. Mol Cell Biol 14, 1383-94.

[0415] Martin, G., Schoonjans, K., Lefebvre, A. M., Staels, B., andAuwerx, J. (1997). Coordinate regulation of the expression of the fattyacid transport protein and acyl-CoA synthetase genes by PPARalpha andPPARgamma activators. J Biol Chem 272, 28210-7.

[0416] Memon, R. A., Fuller, J., Moser, A. H., Smith, P. J., Grunfeld,C., and Feingold, K. R. (1999). Regulation of putative fatty acidtransporters and Acyl-CoA synthetase in liver and adipose tissue inob/ob mice. Diabetes 48, 121-7.

[0417] Motojima, K., Passilly, P., Peters, J. M., Gonzalez, F. J., andLatruffe, N. (1998). Expression of putative fatty acid transporter genesare regulated by peroxisome proliferator-activated receptor alpha andgamma activators in a tissue- and inducer-specific manner. J Biol Chem273, 16710-4.

[0418] Rodenburg, R. J., Holthuizen, P. E., and Sussenbach, J. S.(1997). A functional Sp1 binding site is essential for the activity ofthe adult liver-specific human insulin-like growth factor II promoter.Mol Endocrinol 11, 237-50.

[0419] Rongnoparut, P., Verdon, C. P., Gehnrich, S. C., and Sul, H. S.(1991). Isolation and characterization of the transcriptionallyregulated mouse liver (B-type) phosphofructokinase gene and itspromoter. J Biol Chem 266, 8086-91.

[0420] Ryu, S., Zhou, S., Ladumer, A. G., and Tjian, R. (1999). Thetranscriptional cofactor complex CRSP is required for activity of theenhancer-binding protein Sp1. Nature 397, 446-50.

[0421] Schaffer, J., and Lodish, H. F. (1995). Molecular mechanisms oflong-chain fatty acid uptake. Trends in Cardiovascular Medicine 5,218-224.

[0422] Schaffer, J. E., and Lodish, H. F. (1994). Expression cloning andcharacterization of a novel adipocyte long chain fatty acid transportprotein [see comments]. Cell 79, 427-36.

[0423] Schoonjans, K., Staels, B., and Auwerx, J. (1996). The peroxisomeproliferator activated receptors (PPARS) and their effects on lipidmetabolism and adipocyte differentiation. Biochim Biophys Acta 1302,93-109.

[0424] Sorensen, P., and Wintersberger, E. (1999). Sp1 and NF-Y arenecessary and sufficient for growth-dependent regulation of the hamsterthymidine kinase promoter [In Process Citation]. J Biol Chem 274,30943-9.

[0425] Stahl, A., Hirsch, D. J., Gimeno, R. E., Punreddy, S., Ge, P.,Watson, N., Patel, S., Kotler, M., Raimondi, A., Tartaglia, L. A., andLodish, H. F. (1999). Identification of the major intestinal fatty acidtransport protein [In Process Citation]. Mol Cell 4, 299-308.

[0426] Stremmel, W. (1989). Mechanism of hepatic fatty acid uptake.Journal of Hepatology 9, 374-382.

[0427] All references cited herein are incorporated by reference intheir entirety.

[0428] While this invention has been particularly shown and describedwith references to preferred embodiments thereof, it will be understoodby those skilled in the art that various changes in form and details maybe made therein without departing from the spirit and scope of theinvention as defined by the appended claims.

0 SEQUENCE LISTING <160> NUMBER OF SEQ ID NOS: 140 <210> SEQ ID NO 1<211> LENGTH: 340 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400>SEQUENCE: 1 Phe Ile Phe Thr Ser Gly Thr Thr Gly Leu Pro Lys Pro Ala IleLeu 1 5 10 15 Ser His Glu Arg Val Ile Gln Val Ser Asn Val Leu Ser PheCys Gly 20 25 30 Cys Arg Ala Asp Asp Val Val Tyr Asp Val Leu Pro Leu TyrHis Thr 35 40 45 Ile Gly Leu Val Leu Gly Phe Leu Gly Cys Leu Gln Val GlyAla Thr 50 55 60 Cys Val Leu Ala Pro Lys Phe Ser Ala Ser Arg Phe Trp AlaGlu Cys 65 70 75 80 Arg Gln His Gly Val Thr Val Ile Gln Tyr Ile Gly GluIle Cys Arg 85 90 95 Tyr Leu Leu Arg Gln Pro Val Arg Asp Val Glu Gln ArgHis Arg Val 100 105 110 Arg Leu Ala Val Gly Asn Gly Leu Arg Pro Ala IleTrp Glu Glu Phe 115 120 125 Thr Gln Arg Phe Gly Val Pro Gln Ile Gly GluPhe Tyr Gly Ala Thr 130 135 140 Glu Cys Asn Cys Ser Ile Ala Asn Met AspGly Lys Val Gly Ser Cys 145 150 155 160 Gly Phe Asn Ser Arg Ile Leu ThrHis Val Tyr Pro Ile Arg Leu Val 165 170 175 Lys Val Asn Glu Asp Thr MetGlu Pro Leu Arg Asp Ser Glu Gly Leu 180 185 190 Cys Ile Pro Cys Gln ProGly Glu Pro Gly Leu Leu Val Gly Gln Ile 195 200 205 Asn Gln Gln Asp ProLeu Arg Arg Phe Asp Gly Tyr Val Ser Asp Ser 210 215 220 Ala Thr Asn LysLys Ile Ala His Ser Val Phe Arg Lys Gly Asp Ser 225 230 235 240 Ala TyrLeu Ser Gly Asp Val Leu Val Met Asp Glu Leu Gly Tyr Met 245 250 255 TyrPhe Arg Asp Arg Ser Gly Asp Thr Phe Arg Trp Arg Gly Glu Asn 260 265 270Val Ser Thr Thr Glu Val Glu Ala Val Leu Ser Arg Leu Leu Gly Gln 275 280285 Thr Asp Val Ala Val Tyr Gly Val Ala Val Pro Gly Val Glu Gly Lys 290295 300 Ala Gly Met Ala Ala Ile Ala Asp Pro His Ser Gln Leu Asp Pro Asn305 310 315 320 Ser Met Tyr Gln Glu Leu Gln Lys Val Leu Ala Ser Tyr AlaArg Pro 325 330 335 Ile Phe Leu Arg 340 <210> SEQ ID NO 2 <211> LENGTH:339 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 2 TyrIle Tyr Thr Ser Gly Thr Thr Gly Asn Pro Lys Pro Ala Val Ile 1 5 10 15Lys His Phe Arg Tyr Phe Trp Ile Ala Met Gly Ala Gly Lys Ala Phe 20 25 30Gly Ile Asn Lys Ser Asp Val Val Tyr Ile Thr Met Pro Met Tyr His 35 40 45Ser Ala Ala Gly Ile Met Gly Ile Gly Ser Leu Ile Ala Phe Gly Ser 50 55 60Thr Ala Val Ile Arg Lys Lys Phe Ser Ala Ser Asn Phe Trp Lys Asp 65 70 7580 Cys Val Lys Tyr Asn Val Thr Ala Thr Leu Tyr Val Gly Glu Ile Leu 85 9095 Arg Tyr Leu Cys Asn Val Pro Glu Gln Pro Glu Asp Lys Ile His Thr 100105 110 Val Arg Leu Ala Met Gly Thr Gly Leu Arg Ala Asn Val Trp Lys Asn115 120 125 Phe Gln Gln Arg Phe Gly Pro Ile Arg Ile Trp Glu Phe Tyr GlySer 130 135 140 Thr Glu Gly Asn Val Gly Leu Met Asn Tyr Val Gly His CysGly Ala 145 150 155 160 Val Gly Arg Thr Ser Cys Ile Leu Arg Met Leu ThrPro Phe Glu Leu 165 170 175 Val Gln Phe Asp Ile Glu Thr Ala Glu Pro LeuArg Asp Lys Gln Gly 180 185 190 Phe Cys Ile Pro Val Glu Pro Gly Lys ProGly Leu Leu Leu Thr Lys 195 200 205 Val Arg Lys Asn Gln Pro Phe Leu GlyTyr Arg Gly Ser Gln Ala Glu 210 215 220 Ser Asn Arg Lys Leu Val Ala AsnVal Arg Arg Val Gly Asp Leu Tyr 225 230 235 240 Phe Asn Thr Gly Asp ValLeu Thr Leu Asp Gln Glu Gly Phe Phe Tyr 245 250 255 Phe Gln Asp Arg LeuGly Asp Thr Phe Arg Trp Lys Gly Glu Asn Val 260 265 270 Ser Thr Gly GluVal Glu Cys Val Leu Ser Ser Leu Asp Phe Leu Glu 275 280 285 Glu Val AsnVal Tyr Gly Val Pro Val Pro Gly Cys Glu Gly Lys Val 290 295 300 Gly MetAla Ala Val Lys Leu Ala Pro Gly Lys Thr Phe Asp Gly Lys 305 310 315 320Lys Tyr Gln His Val Arg Ser Trp Leu Pro Ala Tyr Ala Thr Pro His 325 330335 Phe Ile Arg <210> SEQ ID NO 3 <211> LENGTH: 345 <212> TYPE: PRT<213> ORGANISM: Caenorhabditis elegans <400> SEQUENCE: 3 Ile Tyr Thr SerGly Thr Thr Gly Leu Pro Lys Ser Ala Ile Met Ser 1 5 10 15 Trp Arg LysSer Ser Val Gly Cys Gln Val Phe Gly His Val Leu His 20 25 30 Met Thr AsnGlu Ser Thr Val Phe Thr Ala Met Pro Leu Phe His Ser 35 40 45 Thr Ala AlaLeu Leu Gly Ala Cys Ala Ile Leu Ser His Gly Gly Cys 50 55 60 Leu Ala LeuSer His Lys Phe Ser Ala Ser Thr Phe Trp Lys Gln Val 65 70 75 80 Tyr LeuThr Gly Ala Thr His Ile Gln Tyr Ile Gly Glu Ile Cys Arg 85 90 95 Tyr LeuLeu Ala Ala Asn Pro Cys Pro Glu Glu Lys Gln His Asn Val 100 105 110 ArgLeu Met Trp Gly Asn Gly Leu Arg Gly Gln Ile Trp Lys Glu Phe 115 120 125Val Gly Arg Phe Gly Ile Lys Lys Ile Gly Glu Leu Tyr Gly Ser Thr 130 135140 Glu Gly Asn Ser Asn Ile Val Asn Val Asp Asn His Val Gly Ala Cys 145150 155 160 Gly Phe Met Pro Ile Tyr Pro His Ile Gly Ser Leu Tyr Pro ValArg 165 170 175 Leu Ile Lys Val Asp Arg Ala Thr Gly Glu Leu Glu Arg AspLys Asn 180 185 190 Gly Leu Cys Val Pro Cys Val Pro Gly Glu Thr Gly GluMet Val Gly 195 200 205 Val Ile Lys Glu Lys Asp Ile Leu Leu Lys Phe GluGly Tyr Val Ser 210 215 220 Glu Gly Asp Thr Ala Lys Lys Ile Tyr Arg AspVal Phe Lys His Gly 225 230 235 240 Asp Lys Val Phe Ala Ser Gly Asp IleLeu His Trp Asp Asp Leu Gly 245 250 255 Tyr Leu Tyr Phe Val Asp Arg CysGly Asp Thr Phe Arg Trp Lys Gly 260 265 270 Glu Asn Val Ser Thr Thr GluVal Glu Gly Ile Leu Gln Pro Val Met 275 280 285 Asp Val Glu Asp Ala ThrVal Tyr Gly Val Thr Val Gly Lys Met Glu 290 295 300 Gly Arg Ala Gly MetAla Gly Ile Val Val Lys Asp Gly Thr Asp Val 305 310 315 320 Glu Lys PheIle Ala Asp Ile Thr Ser Arg Leu Thr Glu Asn Leu Ala 325 330 335 Ser TyrAla Ile Pro Val Phe Ile Arg 340 345 <210> SEQ ID NO 4 <211> LENGTH: 356<212> TYPE: PRT <213> ORGANISM: Saccharomyces cerevisiae <400> SEQUENCE:4 Tyr Ile Tyr Thr Ser Gly Thr Thr Gly Leu Pro Lys Ala Ala Ile Val 1 5 1015 Val His Ser Arg Tyr Tyr Arg Ile Ala Ala Phe Gly His His Ser Tyr 20 2530 Ser Met Arg Ala Ala Asp Val Leu Tyr Asp Cys Leu Pro Leu Tyr His 35 4045 Ser Ala Gly Asn Ile Met Gly Val Gly Gln Cys Val Ile Tyr Gly Leu 50 5560 Thr Val Val Leu Arg Lys Lys Phe Ser Ala Ser Arg Phe Trp Asp Asp 65 7075 80 Cys Val Lys Tyr Asn Cys Thr Val Val Gln Tyr Val Gly Glu Val Cys 8590 95 Arg Tyr Leu Leu His Thr Pro Ile Ser Lys Tyr Glu Lys Met His Lys100 105 110 Val Lys Val Ala Tyr Gly Asn Gly Leu Arg Pro Asp Ile Trp GlnAsp 115 120 125 Phe Arg Lys Arg Phe Asn Ile Glu Val Ile Gly Glu Phe TyrAla Ala 130 135 140 Thr Glu Ala Pro Phe Ala Thr Thr Thr Phe Gln Lys GlyAsp Phe Gly 145 150 155 160 Ile Gly Ala Cys Arg Asn Tyr Gly Thr Ile IleGln Trp Phe Leu Ser 165 170 175 Phe Gln Gln Thr Leu Val Arg Met Asp ProAsn Asp Asp Ser Val Ile 180 185 190 Tyr Arg Asn Ser Lys Gly Phe Cys GluVal Ala Pro Val Gly Glu Pro 195 200 205 Gly Glu Met Leu Met Arg Ile PhePhe Pro Lys Lys Pro Glu Thr Ser 210 215 220 Phe Gln Gly Tyr Leu Gly AsnAla Lys Glu Thr Lys Ser Lys Val Val 225 230 235 240 Arg Asp Val Phe ArgArg Gly Asp Ala Trp Tyr Arg Cys Gly Asp Leu 245 250 255 Leu Lys Ala AspGlu Tyr Gly Leu Trp Tyr Phe Leu Asp Arg Met Gly 260 265 270 Asp Thr PheArg Trp Lys Ser Glu Asn Val Ser Thr Thr Glu Val Glu 275 280 285 Asp GlnLeu Thr Ala Ser Asn Lys Glu Gln Tyr Ala Gln Val Leu Val 290 295 300 ValGly Ile Lys Val Pro Lys Tyr Glu Gly Arg Ala Gly Phe Ala Val 305 310 315320 Ile Lys Leu Thr Asp Asn Ser Leu Asp Ile Thr Ala Lys Thr Lys Leu 325330 335 Leu Asn Asp Ser Leu Ser Arg Leu Asn Leu Pro Ser Tyr Ala Met Pro340 345 350 Leu Phe Val Lys 355 <210> SEQ ID NO 5 <211> LENGTH: 334<212> TYPE: PRT <213> ORGANISM: Mycobacterium tuberculosis <400>SEQUENCE: 5 Tyr Ile Phe Thr Ser Gly Thr Thr Gly Phe Pro Lys Ala Ser ValMet 1 5 10 15 Thr His His Arg Trp Leu Arg Ala Leu Ala Val Phe Gly GlyMet Gly 20 25 30 Leu Arg Leu Lys Gly Ser Asp Thr Leu Tyr Ser Cys Leu ProLeu Tyr 35 40 45 His Asn Asn Ala Leu Thr Val Ala Val Ser Ser Val Ile AsnSer Gly 50 55 60 Ala Thr Leu Ala Leu Gly Lys Ser Phe Ser Ala Ser Arg PheTrp Asp 65 70 75 80 Glu Val Ile Ala Asn Arg Ala Thr Ala Phe Val Tyr IleGly Glu Ile 85 90 95 Cys Arg Tyr Leu Leu Asn Gln Pro Ala Lys Pro Thr AspArg Ala His 100 105 110 Gln Val Arg Val Ile Cys Gly Asn Gly Leu Arg ProGlu Ile Trp Asp 115 120 125 Glu Phe Thr Thr Arg Phe Gly Val Ala Arg ValCys Glu Phe Tyr Ala 130 135 140 Ala Ser Glu Gly Asn Ser Ala Phe Ile AsnIle Phe Asn Val Pro Arg 145 150 155 160 Thr Ala Gly Val Ser Pro Met ProLeu Ala Phe Val Glu Tyr Asp Leu 165 170 175 Asp Thr Gly Asp Pro Leu ArgAsp Ala Ser Gly Arg Val Arg Arg Val 180 185 190 Pro Asp Gly Glu Pro GlyLeu Leu Leu Ser Arg Val Asn Arg Leu Gln 195 200 205 Pro Phe Asp Gly TyrThr Asp Pro Val Ala Ser Glu Lys Lys Leu Val 210 215 220 Arg Asn Ala PheArg Asp Gly Asp Cys Trp Phe Asn Thr Gly Asp Val 225 230 235 240 Met SerPro Gln Gly Met Gly His Ala Ala Phe Val Asp Arg Leu Gly 245 250 255 AspThr Phe Arg Trp Lys Gly Glu Asn Val Ala Thr Thr Gln Val Glu 260 265 270Ala Ala Leu Ala Ser Asp Gln Thr Val Glu Glu Cys Thr Val Tyr Gly 275 280285 Val Gln Ile Pro Arg Thr Gly Gly Arg Ala Gly Met Ala Ala Ile Thr 290295 300 Leu Arg Ala Gly Ala Glu Phe Asp Gly Gln Ala Leu Ala Arg Thr Val305 310 315 320 Tyr Gly His Leu Pro Gly Tyr Ala Leu Pro Leu Phe Val Arg325 330 <210> SEQ ID NO 6 <211> LENGTH: 2087 <212> TYPE: DNA <213>ORGANISM: Mus musculus <400> SEQUENCE: 6 acgactcact atagggagagagctatgacg tcgcatgcac gcgtaagctt gggcccctcg 60 agggatcctc tagagcggccgccgaccccg aaagctctga gagcgggtgc agtctggcct 120 ggcgtctcgc gtacctggcccgggagcagc cgacacacac cttcctcatc cacggcgcgc 180 agcgctttag ctacgcggaggctgagcgcg agagcaaccg gattgctcgc gcctttctgc 240 gcgcacgggg ctggaccgggggccgccgag gctcgggcag gggcagcact gaggaaggcg 300 cacgcgtggc gcctccggctggagatgcgg ctgctagagg gacgaccgcg ccccctctgg 360 cacccggggc gaccgtggcgctgctcctcc cagcgggccc ggatttcctt tggatttggt 420 tcggactggc caaagctggcctgcgcacgg cctttgtgcc caccgcttta cgccgaggac 480 ccctgctgca ctgcctccgcagctgcggtg cgagtgcgct cgtgctggcc acagagttcc 540 tggagtccct ggagccggacctgccggcct tgagagccat ggggctccac ctatgggcga 600 cgggccctga aactaatgtagctggaatca gcaatttgct atcggaagca gcagaccaag 660 tggatgagcc agtgccggggtacctctctg ccccccagaa cataatggac acctgcctgt 720 acatcttcac ctctggcactactggcctgc ccaaggctgc tcgaatcagt catctgaagg 780 ttctacagtg ccagggattctaccatctgt gtggagtcca ccaggaggac gtgatctacc 840 tcgcactccc actgtaccacatgtctggct cccttctggg cattgtgggc tgcttgggca 900 ttggggccac cgtggtgctgaaacccaagt tctcagctag ccagttctgg gacgattgcc 960 agaaacacag ggtgacagtgttccagtaca ttggggagtt gtgccgatac ctcgtcaacc 1020 agcccccgag caaggcagagtttgaccata aggtgcgctt ggcagtgggc agtgggttgc 1080 gcccagacac ctgggagcgtttcctgcggc gatttggacc tctgcagata ctggagacgt 1140 atggcatgac agagggcaacgtagctacgt tcaattacac aggacggcag ggtgcagtgg 1200 ggcgagcttc ctggctttacaagcacatct tccccttctc cttgattcga tacgatgtca 1260 tgacagggga gcctattcggaatgcccagg ggcactgcat gaccacatct ccaggtgagc 1320 caggcctact ggtggccccagtgagccagc agtccccctt cctgggctat gctggggctc 1380 cggagctggc caaggacaagctgctgaagg atgtcttctg gtctggggac gttttcttca 1440 atactgggga cctcttggtctgtgatgagc aaggctttct tcacttccac gatcgtactg 1500 gagacaccat caggtggaagggagagaatg tggccacaac tgaagtggct gaggtcttgg 1560 agaccctgga cttccttcaggaggtgaaca tctatggagt cacggtgcca gggcacgaag 1620 gcagggcagg catggcggccttggctctgc ggcccccgca ggctctgaac ctggtgcagc 1680 tctacagcca tgtttctgagaacttgccac cgtatgcccg acctcggttt ctcaggctcc 1740 aggaatcttt ggccactactgagaccttca aacagcagaa ggttaggatg gccaatgagg 1800 gctttgaccc cagtgtactgtctgacccac tctatgttct ggaccaagat ataggggcct 1860 acctgcccct cacacctgcccggtacagtg ccctcctgtc tggagacctt cgaatctgaa 1920 accttccact tgagggaggggctcggaggg tacaggccac catggctgca ccagggaggg 1980 ttttcgggta tcttttgtatatggagtcat tattttgtaa taaacagctg gagcttaaaa 2040 aaaaaaaaaa aaaaaaaaaaaaaaaaaaaa aaaaaaaaaa aaaaaaa 2087 <210> SEQ ID NO 7 <211> LENGTH: 613<212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 7 Ala AlaAsp Pro Glu Ser Ser Glu Ser Gly Cys Ser Leu Ala Trp Arg 1 5 10 15 LeuAla Tyr Leu Ala Arg Glu Gln Pro Thr His Thr Phe Leu Ile His 20 25 30 GlyAla Gln Arg Phe Ser Tyr Ala Glu Ala Glu Arg Glu Ser Asn Arg 35 40 45 IleAla Arg Ala Phe Leu Arg Ala Arg Gly Trp Thr Gly Gly Arg Arg 50 55 60 GlySer Gly Arg Gly Ser Thr Glu Glu Gly Ala Arg Val Ala Pro Pro 65 70 75 80Ala Gly Asp Ala Ala Ala Arg Gly Thr Thr Ala Pro Pro Leu Ala Pro 85 90 95Gly Ala Thr Val Ala Leu Leu Leu Pro Ala Gly Pro Asp Phe Leu Trp 100 105110 Ile Trp Phe Gly Leu Ala Lys Ala Gly Leu Arg Thr Ala Phe Val Pro 115120 125 Thr Ala Leu Arg Arg Gly Pro Leu Leu His Cys Leu Arg Ser Cys Gly130 135 140 Ala Ser Ala Leu Val Leu Ala Thr Glu Phe Leu Glu Ser Leu GluPro 145 150 155 160 Asp Leu Pro Ala Leu Arg Ala Met Gly Leu His Leu TrpAla Thr Gly 165 170 175 Pro Glu Thr Asn Val Ala Gly Ile Ser Asn Leu LeuSer Glu Ala Ala 180 185 190 Asp Gln Val Asp Glu Pro Val Pro Gly Tyr LeuSer Ala Pro Gln Asn 195 200 205 Ile Met Asp Thr Cys Leu Tyr Ile Phe ThrSer Gly Thr Thr Gly Leu 210 215 220 Pro Lys Ala Ala Arg Ile Ser His LeuLys Val Leu Gln Cys Gln Gly 225 230 235 240 Phe Tyr His Leu Cys Gly ValHis Gln Glu Asp Val Ile Tyr Leu Ala 245 250 255 Leu Pro Leu Tyr His MetSer Gly Ser Leu Leu Gly Ile Val Gly Cys 260 265 270 Leu Gly Ile Gly AlaThr Val Val Leu Lys Pro Lys Phe Ser Ala Ser 275 280 285 Gln Phe Trp AspAsp Cys Gln Lys His Arg Val Thr Val Phe Gln Tyr 290 295 300 Ile Gly GluLeu Cys Arg Tyr Leu Val Asn Gln Pro Pro Ser Lys Ala 305 310 315 320 GluPhe Asp His Lys Val Arg Leu Ala Val Gly Ser Gly Leu Arg Pro 325 330 335Asp Thr Trp Glu Arg Phe Leu Arg Arg Phe Gly Pro Leu Gln Ile Leu 340 345350 Glu Thr Tyr Gly Met Thr Glu Gly Asn Val Ala Thr Phe Asn Tyr Thr 355360 365 Gly Arg Gln Gly Ala Val Gly Arg Ala Ser Trp Leu Tyr Lys His Ile370 375 380 Phe Pro Phe Ser Leu Ile Arg Tyr Asp Val Met Thr Gly Glu ProIle 385 390 395 400 Arg Asn Ala Gln Gly His Cys Met Thr Thr Ser Pro GlyGlu Pro Gly 405 410 415 Leu Leu Val Ala Pro Val Ser Gln Gln Ser Pro PheLeu Gly Tyr Ala 420 425 430 Gly Ala Pro Glu Leu Ala Lys Asp Lys Leu LeuLys Asp Val Phe Trp 435 440 445 Ser Gly Asp Val Phe Phe Asn Thr Gly AspLeu Leu Val Cys Asp Glu 450 455 460 Gln Gly Phe Leu His Phe His Asp ArgThr Gly Asp Thr Ile Arg Trp 465 470 475 480 Lys Gly Glu Asn Val Ala ThrThr Glu Val Ala Glu Val Leu Glu Thr 485 490 495 Leu Asp Phe Leu Gln GluVal Asn Ile Tyr Gly Val Thr Val Pro Gly 500 505 510 His Glu Gly Arg AlaGly Met Ala Ala Leu Ala Leu Arg Pro Pro Gln 515 520 525 Ala Leu Asn LeuVal Gln Leu Tyr Ser His Val Ser Glu Asn Leu Pro 530 535 540 Pro Tyr AlaArg Pro Arg Phe Leu Arg Leu Gln Glu Ser Leu Ala Thr 545 550 555 560 ThrGlu Thr Phe Lys Gln Gln Lys Val Arg Met Ala Asn Glu Gly Phe 565 570 575Asp Pro Ser Val Leu Ser Asp Pro Leu Tyr Val Leu Asp Gln Asp Ile 580 585590 Gly Ala Tyr Leu Pro Leu Thr Pro Ala Arg Tyr Ser Ala Leu Leu Ser 595600 605 Gly Asp Leu Arg Ile 610 <210> SEQ ID NO 8 <211> LENGTH: 2301<212> TYPE: DNA <213> ORGANISM: Mus musculus <400> SEQUENCE: 8cccacgcgtc cgcccacgcg tccggcatgg ccaagctggg cgtggaggcg gctctcatca 60acaccaacct taggcgggat gccctgcgcc actgtcttga cacctcaaag gcacgagctc 120tcatctttgg cagtgagatg gcctcagcta tctgtgagat ccatgctagc ctggagccca 180cactcagcct cttctgctct ggatcctggg agcccagcac agtgcccgtc agcacagagc 240atctggaccc tcttctggaa gatgccccga agcacctgcc cagtcaccca gacaagggtt 300ttacagataa gctcttctac atctacacat cgggcaccac ggggctaccc aaagctgcca 360ttgtggtgca cagcaggtat tatcgtatgg cttccctggt gtactatgga ttccgcatgc 420ggcctgatga cattgtctat gactgcctcc ccctctacca ctcaagcagg aaacatcgtg 480gggattggca gtgcttactc cacggcatga ctgtggtgat ccggaagaag ttctcagcct 540cccggttctg ggatgattgt atcaagtaca actgcacagt ggtacagtac attggcgagc 600tctgccgcta cctcctgaac cagccacccc gtgaggctga gtctcggcac aaggtgcgca 660tggcactggg caacggtctc cggcagtcca tctggaccga cttctccagc cgtttccaca 720tcccccaggt ggctgagttc tatggggcca ctgaatgcaa ctgtagcctg ggcaactttg 780acagccgggt gggggcctgt ggcttcaata gccgcatcct gtcctttgtg taccctatcc 840gtttggtacg tgtcaatgag gataccatgg aactgatccg gggacccgat ggagtctgca 900ttccctgtca accaggtcag ccaggccagc tggtgggtcg catcatccag caggaccctc 960tgcgccgttt cgacgggtac ctcaaccagg gtgccaacaa caagaagatt gctaatgatg 1020tcttcaagaa gggggaccaa gcctacctca ctggtgacgt cctggtgatg gatgagctgg 1080gttacctgta cttccgagat cgcactgggg acacgttccg ctggaaaggg gagaatgtat 1140ctaccactga ggtggagggc acactcagcc gcctgcttca tatggcagat gtggcagttt 1200atggtgttga ggtgccagga actgaaggcc gagcaggaat ggctgccgtt gcaagtccca 1260tcagcaactg tgacctggag agctttgcac agaccttgaa aaaggagctg cctctgtatg 1320cccgccccat cttcctgcgc ttcttgcctg agctgcacaa gacagggacc ttcaagttcc 1380agaagacaga gttgcggaag gagggctttg acccatctgt tgtgaaagac ccgctgttct 1440atctggatgc tcggaagggc tgctacgttg cactggacca ggaggcctat acccgcatcc 1500aggcaggcga ggagaagctg tgatttcccc ctacatccct ctgagggcca gaagatgctg 1560gattcagagc cctagcgtcc accccagagg gtcctgggca atgccagacc aaagctagca 1620gggcccgcac ctccgcccct aggtgctgat ctcccctctc ccaaactgcc aagtgactca 1680ctgccgcttc cccgaccctc cagaggcttt ctgtgaaagt ctcatccaag ctgtgtcttc 1740tggtccaggc gtggcccctg gccccagggt ttctgatagg ctcctttagg atggtatctt 1800gggtccagcg ggccagggtg tgggagagga gtcactaaga tccctccaat cagaagggag 1860cttacaaagg aaccaaggca aagcctgtag actcaggaag ctaagtggcc agagactata 1920gtggccagtc atcccatgtc cacagaggat cttggtccag agctgccaaa gtgtcacctc 1980tccctgcctg cacctctggg gaaaagagga cagcatgtgg ccactgggca cctgtctcaa 2040gaagtcagga tcacacactc agtccttgtt tctccaggtt cccttgttct tgtctcgggg 2100agggagggac gagtgtcctg tctgtccttc ctgcctgtct gtgagtctgt gttgcttctc 2160catctgtcct agcctgagtg tgggtggaac aggcatgagg agagtgtggc tcaggggcca 2220ataaactctg ccttgactcc tcttaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 2280aaaaaaaaaa aaaaaaaaaa a 2301 <210> SEQ ID NO 9 <211> LENGTH: 506 <212>TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 9 His Ala Ser AlaHis Ala Ser Gly Met Ala Lys Leu Gly Val Glu Ala 1 5 10 15 Ala Leu IleAsn Thr Asn Leu Arg Arg Asp Ala Leu Arg His Cys Leu 20 25 30 Asp Thr SerLys Ala Arg Ala Leu Ile Phe Gly Ser Glu Met Ala Ser 35 40 45 Ala Ile CysGlu Ile His Ala Ser Leu Glu Pro Thr Leu Ser Leu Phe 50 55 60 Cys Ser GlySer Trp Glu Pro Ser Thr Val Pro Val Ser Thr Glu His 65 70 75 80 Leu AspPro Leu Leu Glu Asp Ala Pro Lys His Leu Pro Ser His Pro 85 90 95 Asp LysGly Phe Thr Asp Lys Leu Phe Tyr Ile Tyr Thr Ser Gly Thr 100 105 110 ThrGly Leu Pro Lys Ala Ala Ile Val Val His Ser Arg Tyr Tyr Arg 115 120 125Met Ala Ser Leu Val Tyr Tyr Gly Phe Arg Met Arg Pro Asp Asp Ile 130 135140 Val Tyr Asp Cys Leu Pro Leu Tyr His Ser Ser Arg Lys His Arg Gly 145150 155 160 Asp Trp Gln Cys Leu Leu His Gly Met Thr Val Val Ile Arg LysLys 165 170 175 Phe Ser Ala Ser Arg Phe Trp Asp Asp Cys Ile Lys Tyr AsnCys Thr 180 185 190 Val Val Gln Tyr Ile Gly Glu Leu Cys Arg Tyr Leu LeuAsn Gln Pro 195 200 205 Pro Arg Glu Ala Glu Ser Arg His Lys Val Arg MetAla Leu Gly Asn 210 215 220 Gly Leu Arg Gln Ser Ile Trp Thr Asp Phe SerSer Arg Phe His Ile 225 230 235 240 Pro Gln Val Ala Glu Phe Tyr Gly AlaThr Glu Cys Asn Cys Ser Leu 245 250 255 Gly Asn Phe Asp Ser Arg Val GlyAla Cys Gly Phe Asn Ser Arg Ile 260 265 270 Leu Ser Phe Val Tyr Pro IleArg Leu Val Arg Val Asn Glu Asp Thr 275 280 285 Met Glu Leu Ile Arg GlyPro Asp Gly Val Cys Ile Pro Cys Gln Pro 290 295 300 Gly Gln Pro Gly GlnLeu Val Gly Arg Ile Ile Gln Gln Asp Pro Leu 305 310 315 320 Arg Arg PheAsp Gly Tyr Leu Asn Gln Gly Ala Asn Asn Lys Lys Ile 325 330 335 Ala AsnAsp Val Phe Lys Lys Gly Asp Gln Ala Tyr Leu Thr Gly Asp 340 345 350 ValLeu Val Met Asp Glu Leu Gly Tyr Leu Tyr Phe Arg Asp Arg Thr 355 360 365Gly Asp Thr Phe Arg Trp Lys Gly Glu Asn Val Ser Thr Thr Glu Val 370 375380 Glu Gly Thr Leu Ser Arg Leu Leu His Met Ala Asp Val Ala Val Tyr 385390 395 400 Gly Val Glu Val Pro Gly Thr Glu Gly Arg Ala Gly Met Ala AlaVal 405 410 415 Ala Ser Pro Ile Ser Asn Cys Asp Leu Glu Ser Phe Ala GlnThr Leu 420 425 430 Lys Lys Glu Leu Pro Leu Tyr Ala Arg Pro Ile Phe LeuArg Phe Leu 435 440 445 Pro Glu Leu His Lys Thr Gly Thr Phe Lys Phe GlnLys Thr Glu Leu 450 455 460 Arg Lys Glu Gly Phe Asp Pro Ser Val Val LysAsp Pro Leu Phe Tyr 465 470 475 480 Leu Asp Ala Arg Lys Gly Cys Tyr ValAla Leu Asp Gln Glu Ala Tyr 485 490 495 Thr Arg Ile Gln Ala Gly Glu GluLys Leu 500 505 <210> SEQ ID NO 10 <211> LENGTH: 2277 <212> TYPE: DNA<213> ORGANISM: Mus musculus <400> SEQUENCE: 10 cactcatcag agctaagagagactacacgc tctcatctac ttcagaaaga gccaatgcca 60 tgggtatttg gaagaaactaaccttactgc tgttgctgct tctgctggtt ggcctggggc 120 agcccccatg gccagcagctatggctctgg ccctgcgttg gttcctggga gaccccacat 180 gccttgtgct gcttggcttggcattgctgg gcagaccctg gatcagctcc tggatgcccc 240 actggctgag cctggtaggagcagctctta ccttattcct attgcctcta cagccacccc 300 cagggctacg ctggctgcataaagatgtgg ctttcacctt caagatgctt ttctatggcc 360 taaagttcag gcgacgccttaacaaacatc ctccagagac ctttgtggat gctttagagc 420 ggcaagcact ggcatggcctgaccgggtgg ccttggtgtg tactgggtct gagggctcct 480 caatcacaaa tagccagctggatgccaggt cctgtcaggc agcatgggtc ctgaaagcaa 540 agctgaagga tgccgtaatccagaacacaa gagatgctgc tgctatctta gttctcccgt 600 ccaagaccat ttctgctttgagtgtgtttc tggggttggc caagttgggc tgccctgtgg 660 cctggatcaa tccacacagccgagggatgc ccttgctaca ctctgtacgg agctctgggg 720 ccagtgtgct gattgtggatccagacctcc aggagaacct ggaagaagtc cttcccaagc 780 tgctagctga gaacattcactgcttctacc ttggccacag ctcacccacc ccgggagtag 840 aggctctggg agcttccctggatgctgcac cttctgaccc agtacctgcc agccttcgag 900 ctacgattaa gtggaaatctcctgccatat tcatctttac ttcagggacc actggactcc 960 caaagccagc catcttatcacatgagcggg tcatacaagt gagcaacgtg ctgtccttct 1020 gtggatgcag agctgatgatgtggtctatg acgtcctacc tctgtaccat acgatagggc 1080 ttgtccttgg attccttggctgcttacaag ttggagccac ctgtgtcctg gcccccaagt 1140 tctctgcctc ccgattctgggctgagtgcc ggcagcatgg cgtaacagtg atcttgtatg 1200 tgggtgaaat cctgcggtacttgtgtaacg tccctgagca accagaagac aagatacata 1260 cagtgcgctt ggccatgggaactggacttc gggcaaatgt gtggaaaaac ttccagcaac 1320 gctttggtcc cattcggatctgggaattct acggatccac agagggcaat gtgggcttaa 1380 tgaactatgt gggccactgcggggctgtgg gaaggaccag ctgcatcctt cgaatgctga 1440 ctccctttga gcttgtacagttcgacatag agacagcaga gcctctgagg gacaaacagg 1500 gtttttgcat tcctgtggagccaggaaagc caggacttct tttgaccaag gttcgaaaga 1560 accaaccctt cctgggctaccgtggttccc aggccgagtc caatcggaaa cttgttgcga 1620 atgtacgacg cgtaggagacctgtacttca acactgggga cgtgctgacc ttggaccagg 1680 aaggcttctt ctactttcaagaccgccttg gtgacacctt ccggtggaag ggcgaaaacg 1740 tatctactgg agaggtggagtgtgttttgt ctagcctaga cttcctagag gaagtcaatg 1800 tctatggtgt gcctgtgccagggtgtgagg gtaaggttgg catggctgct gtgaaactgg 1860 ctcctgggaa gacttttgatgggcagaagc tataccagca tgtccgctcc tggctccctg 1920 cctatgccac acctcatttcatccgtatcc aggattccct ggagatcaca aacacctaca 1980 agctggtaaa gtcacggctggtgcgtgagg gttttgatgt ggggatcatt gctgaccccc 2040 tctacatact ggacaacaaggcccagacct tccggagtct gatgccagat gtgtaccagg 2100 ctgtgtgtga aggaacctggaatctctgac cacctagcca actggaaggc aatccaaaag 2160 tgtagagatt gacactagtcagcttcacaa agttgtccgg gttccagatg cccatggccc 2220 agtagtactt agagaataaacttgaatgtg tatacaaaaa aaaaaaaaaa aaaaaaa 2277 <210> SEQ ID NO 11 <211>LENGTH: 662 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE:11 Met Ala Leu Ala Leu Arg Trp Phe Leu Gly Asp Pro Thr Cys Leu Val 1 510 15 Leu Leu Gly Leu Ala Leu Leu Gly Arg Pro Trp Ile Ser Ser Trp Met 2025 30 Pro His Trp Leu Ser Leu Val Gly Ala Ala Leu Thr Leu Phe Leu Leu 3540 45 Pro Leu Gln Pro Pro Pro Gly Leu Arg Trp Leu His Lys Asp Val Ala 5055 60 Phe Thr Phe Lys Met Leu Phe Tyr Gly Leu Lys Phe Arg Arg Arg Leu 6570 75 80 Asn Lys His Pro Pro Glu Thr Phe Val Asp Ala Leu Glu Arg Gln Ala85 90 95 Leu Ala Trp Pro Asp Arg Val Ala Leu Val Cys Thr Gly Ser Glu Gly100 105 110 Ser Ser Ile Thr Asn Ser Gln Leu Asp Ala Arg Ser Cys Gln AlaAla 115 120 125 Trp Val Leu Lys Ala Lys Leu Lys Asp Ala Val Ile Gln AsnThr Arg 130 135 140 Asp Ala Ala Ala Ile Leu Val Leu Pro Ser Lys Thr IleSer Ala Leu 145 150 155 160 Ser Val Phe Leu Gly Leu Ala Lys Leu Gly CysPro Val Ala Trp Ile 165 170 175 Asn Pro His Ser Arg Gly Met Pro Leu LeuHis Ser Val Arg Ser Ser 180 185 190 Gly Ala Ser Val Leu Ile Val Asp ProAsp Leu Gln Glu Asn Leu Glu 195 200 205 Glu Val Leu Pro Lys Leu Leu AlaGlu Asn Ile His Cys Phe Tyr Leu 210 215 220 Gly His Ser Ser Pro Thr ProGly Val Glu Ala Leu Gly Ala Ser Leu 225 230 235 240 Asp Ala Ala Pro SerAsp Pro Val Pro Ala Ser Leu Arg Ala Thr Ile 245 250 255 Lys Trp Lys SerPro Ala Ile Phe Ile Phe Thr Ser Gly Thr Thr Gly 260 265 270 Leu Pro LysPro Ala Ile Leu Ser His Glu Arg Val Ile Gln Val Ser 275 280 285 Asn ValLeu Ser Phe Cys Gly Cys Arg Ala Asp Asp Val Val Tyr Asp 290 295 300 ValLeu Pro Leu Tyr His Thr Ile Gly Leu Val Leu Gly Phe Leu Gly 305 310 315320 Cys Leu Gln Val Gly Ala Thr Cys Val Leu Ala Pro Lys Phe Ser Ala 325330 335 Ser Arg Phe Trp Ala Glu Cys Arg Gln His Gly Val Thr Val Ile Leu340 345 350 Tyr Val Gly Glu Ile Leu Arg Tyr Leu Cys Asn Val Pro Glu GlnPro 355 360 365 Glu Asp Lys Ile His Thr Val Arg Leu Ala Met Gly Thr GlyLeu Arg 370 375 380 Ala Asn Val Trp Lys Asn Phe Gln Gln Arg Phe Gly ProIle Arg Ile 385 390 395 400 Trp Glu Phe Tyr Gly Ser Thr Glu Gly Asn ValGly Leu Met Asn Tyr 405 410 415 Val Gly His Cys Gly Ala Val Gly Arg ThrSer Cys Ile Leu Arg Met 420 425 430 Leu Thr Pro Phe Glu Leu Val Gln PheAsp Ile Glu Thr Ala Glu Pro 435 440 445 Leu Arg Asp Lys Gln Gly Phe CysIle Pro Val Glu Pro Gly Lys Pro 450 455 460 Gly Leu Leu Leu Thr Lys ValArg Lys Asn Gln Pro Phe Leu Gly Tyr 465 470 475 480 Arg Gly Ser Gln AlaGlu Ser Asn Arg Lys Leu Val Ala Asn Val Arg 485 490 495 Arg Val Gly AspLeu Tyr Phe Asn Thr Gly Asp Val Leu Thr Leu Asp 500 505 510 Gln Glu GlyPhe Phe Tyr Phe Gln Asp Arg Leu Gly Asp Thr Phe Arg 515 520 525 Trp LysGly Glu Asn Val Ser Thr Gly Glu Val Glu Cys Val Leu Ser 530 535 540 SerLeu Asp Phe Leu Glu Glu Val Asn Val Tyr Gly Val Pro Val Pro 545 550 555560 Gly Cys Glu Gly Lys Val Gly Met Ala Ala Val Lys Leu Ala Pro Gly 565570 575 Lys Thr Phe Asp Gly Gln Lys Leu Tyr Gln His Val Arg Ser Trp Leu580 585 590 Pro Ala Tyr Ala Thr Pro His Phe Ile Arg Ile Gln Asp Ser LeuGlu 595 600 605 Ile Thr Asn Thr Tyr Lys Leu Val Lys Ser Arg Leu Val ArgGlu Gly 610 615 620 Phe Asp Val Gly Ile Ile Ala Asp Pro Leu Tyr Ile LeuAsp Asn Lys 625 630 635 640 Ala Gln Thr Phe Arg Ser Leu Met Pro Asp ValTyr Gln Ala Val Cys 645 650 655 Glu Gly Thr Trp Asn Leu 660 <210> SEQ IDNO 12 <211> LENGTH: 1622 <212> TYPE: DNA <213> ORGANISM: Homo sapiens<220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(1622)<223> OTHER INFORMATION: n = A,T,C or G <220> FEATURE: <221> NAME/KEY:misc_feature <222> LOCATION: 998, 1022, 1027, 1078, 1094, 1121, 1128,1202, 1275, 1292,1308 <223> OTHER INFORMATION: n = A,T,C or G <400>SEQUENCE: 12 atgggattga ctctttcctg gacaaagtgg atgaagtatc aactgaacctatcccagagt 60 catggaggtc tgaagtcact ttttccactc ctgccttata catttatacttctggaacca 120 caggtcttcc aaaagcagcc atgatcactc atcagcgcat atggtatggaactggcctca 180 cttttgtaag cggattgaag gcagatgatg tcatctatat cactctgcccttttaccaca 240 gtgctgcact actgattggc attcacggat gtattgtggc tggtgctactcttgccttgc 300 ggactaaatt ttcagccagc cagttttggg atgactgcag aaaatacaacgtcactgtca 360 ttcagtatat cggtgaactg cttcggtatt tatgcaactc accacagaaaccaaatgacc 420 gtgatcataa agtgagactg gcactgggaa atggcttacg aggagatgtgtggagacaat 480 ttgtcaagag atttggggac atatgcatct atgagttcta tgctgccactgaaggcaata 540 ttggatttat gaattatgcg agaaaagttg gtgctgttgg aagagtaaactacctacaga 600 aaaaaatcat aacttatgac ctgattaaat atgatgtgga gaaagatgaacctgtccgtg 660 atgaaaatgg atattgcgtc agagttccca aaggtgaagt tggacttctggtttgcaaaa 720 tcacacaact tacaccattt aatggctatg ctggagcaaa ggctcagacagagaagaaaa 780 aactgagaga tgtctttaag aaaggagacc tctatttcaa cagtggagatctcttaatgg 840 ttgaccatga aaatttcatc tatttccacg acagagttgg agatacattccggtggaaag 900 gggaaaatgt ggccaccact gaagttgctg atatagttgg actggttgatttttttccaa 960 ggaagtaaaa tgtttatggg agtgcatggg ccaagatnat ggaggttcgaattggcatgg 1020 cnttccnttc aaaatggaaa gaaaaccatg gaatttgatg gaaagaaattttttcagnac 1080 attgctgata accnacctag ttatgcaagg ccccggtttt ntaagaanacaggacaccat 1140 tgagatcact ggaattttta aacaccgcaa aatgaccttt ggtggaggagggctttaacc 1200 cngctgtcat caaagatgcc ttgtattttc ttggatgaca cagcaaaaatgtatgtgcct 1260 atgactgagg acatntataa tgccataagt gntaaaaccc tgaaattntgaatattccca 1320 ggaggataat tcaacatttc cagaaagaaa ctgaatggac agccacttgatataatccaa 1380 ctttaatttg attgaagatt gtgaggaaat tttgtaggaa atttgcatacccgtaaaggg 1440 agactttttt aaataacagt tgagtctttg caagtaaaaa gatttagagattattatttt 1500 tcagtgtgca cctactgttt gtatttgcaa actgagcttg ttggagggaaggcattattt 1560 tttaaaatac ttagtaaatt aaagaacacc aacatgtgaa aaaaaaaaaaaaaaaaaaaa 1620 aa 1622 <210> SEQ ID NO 13 <211> LENGTH: 286 <212> TYPE:PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 13 Tyr Ile Tyr Thr SerGly Thr Thr Gly Leu Pro Lys Ala Ala Met Ile 1 5 10 15 Thr His Gln ArgIle Trp Tyr Gly Thr Gly Leu Thr Phe Val Ser Gly 20 25 30 Leu Lys Ala AspAsp Val Ile Tyr Ile Thr Leu Pro Phe Tyr His Ser 35 40 45 Ala Ala Leu LeuIle Gly Ile His Gly Cys Ile Val Ala Gly Ala Thr 50 55 60 Leu Ala Leu ArgThr Lys Phe Ser Ala Ser Gln Phe Trp Asp Asp Cys 65 70 75 80 Arg Lys TyrAsn Val Thr Val Ile Gln Tyr Ile Gly Glu Leu Leu Arg 85 90 95 Tyr Leu CysAsn Ser Pro Gln Lys Pro Asn Asp Arg Asp His Lys Val 100 105 110 Arg LeuAla Leu Gly Asn Gly Leu Arg Gly Asp Val Trp Arg Gln Phe 115 120 125 ValLys Arg Phe Gly Asp Ile Cys Ile Tyr Glu Phe Tyr Ala Ala Thr 130 135 140Glu Gly Asn Ile Gly Phe Met Asn Tyr Ala Arg Lys Val Gly Ala Val 145 150155 160 Gly Arg Val Asn Tyr Leu Gln Lys Lys Ile Ile Thr Tyr Asp Leu Ile165 170 175 Lys Tyr Asp Val Glu Lys Asp Glu Pro Val Arg Asp Glu Asn GlyTyr 180 185 190 Cys Val Arg Val Pro Lys Gly Glu Val Gly Leu Leu Val CysLys Ile 195 200 205 Thr Gln Leu Thr Pro Phe Asn Gly Tyr Ala Gly Ala LysAla Gln Thr 210 215 220 Glu Lys Lys Lys Leu Arg Asp Val Phe Lys Lys GlyAsp Leu Tyr Phe 225 230 235 240 Asn Ser Gly Asp Leu Leu Met Val Asp HisGlu Asn Phe Ile Tyr Phe 245 250 255 His Asp Arg Val Gly Asp Thr Phe ArgTrp Lys Gly Glu Asn Val Ala 260 265 270 Thr Thr Glu Val Ala Asp Ile ValGly Leu Val Asp Phe Phe 275 280 285 <210> SEQ ID NO 14 <211> LENGTH: 753<212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 14caattcggga cccccagggg cactgtatgg ccacatctcc aggtgagcca ggggaagttg 60ctaaaggatg tcttccggcc tggggatgtt ttcttcaaca ctggggacct gctggtctgc 120gatgaccaag gttttctccg cttccatgat cgtactggag acaccttcag gtggaaaggg 180gagaatgtgg ccacaaccga ggtggcagag gtcttcgagg ccctagattt tcttcaggag 240gtgaacgtct atggagtcac tgtgccaggg catgaaggca gggctggaat ggcagcccta 300gttctgcgtc ccccccacgc tttggacctt atgcagctct acacccacgt gtctgagaac 360ttgccacctt atgcccggcc ccgattcctc aggctccagg agtctttggc caccacagag 420accttcaaac agcagaaagt tcggatggca aatgagggct tcgaccccag caccctgtct 480gacccactgt acgttctgga ccaggctgta ggtgcctacc tgcccctcac aactgcccgg 540tacagcgccc tcctggcagg aaaccttcga atctgagaac ttccacacct gaggcacctg 600agagaggaac tctgtggggt gggggccgtt gcaggtgtac tgggctgtca gggatctttt 660ctataccaga actgcggtca ctattttgta ataaatgtgg ctggagctga tccagctgtc 720tctgacctac aaaaaaaaaa aaaaaaaaaa aaa 753 <210> SEQ ID NO 15 <211>LENGTH: 191 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:15 Gln Phe Gly Thr Pro Arg Gly Thr Val Trp Pro His Leu Gln Val Ser 1 510 15 Gln Gly Lys Leu Leu Lys Asp Val Phe Arg Pro Gly Asp Val Phe Phe 2025 30 Asn Thr Gly Asp Leu Leu Val Cys Asp Asp Gln Gly Phe Leu Arg Phe 3540 45 His Asp Arg Thr Gly Asp Thr Phe Arg Trp Lys Gly Glu Asn Val Ala 5055 60 Thr Thr Glu Val Ala Glu Val Phe Glu Ala Leu Asp Phe Leu Gln Glu 6570 75 80 Val Asn Val Tyr Gly Val Thr Val Pro Gly His Glu Gly Arg Ala Gly85 90 95 Met Ala Ala Leu Val Leu Arg Pro Pro His Ala Leu Asp Leu Met Gln100 105 110 Leu Tyr Thr His Val Ser Glu Asn Leu Pro Pro Tyr Ala Arg ProArg 115 120 125 Phe Leu Arg Leu Gln Glu Ser Leu Ala Thr Thr Glu Thr PheLys Gln 130 135 140 Gln Lys Val Arg Met Ala Asn Glu Gly Phe Asp Pro SerThr Leu Ser 145 150 155 160 Asp Pro Leu Tyr Val Leu Asp Gln Ala Val GlyAla Tyr Leu Pro Leu 165 170 175 Thr Thr Ala Arg Tyr Ser Ala Leu Leu AlaGly Asn Leu Arg Ile 180 185 190 <210> SEQ ID NO 16 <211> LENGTH: 734<212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221>NAME/KEY: misc_feature <222> LOCATION: (1)...(734) <223> OTHERINFORMATION: n = A,T,C or G <220> FEATURE: <221> NAME/KEY: misc_feature<222> LOCATION: 27, 46 <223> OTHER INFORMATION: n = A,T,C or G <400>SEQUENCE: 16 tcaagtacaa ctgcacgatt gtcatancat tggtgaactg tgccgntacctcctgaacca 60 gccaccgcgg gaggcagaaa accagcacca ggttcgcatg gcactaggcaatggcctccg 120 gcagtccatc tggaccaact tttccagccg cttccacata ccccaggtggctgagttyta 180 cggggccaca gagtgcaact gtagcctggg caacttcgac agccaggtgggggcctgtgg 240 tttcaatagc cgcatcctgt ccttcgtgta ccccatccgg ttggtacgtgtcaacgagga 300 caccatggag ctgatccggg ggcccgacgg cgtctgcatt ccctgccagccaggtgagcc 360 gggccagctg gtgggccgca tcatccagaa agaccccctg cgccgcttcgatggctacct 420 caaccagggc gccaacaaca agaagattgc caaggatgtc ttcaagaagggggaccaggc 480 ctaccttact ggtgatgtgc tggtgatgga cgagctgggc tacctgtacttccgagaccg 540 cactggggac acgttccgct ggaaaggtga gaacgtgtcc accaccgaggtggaaggcac 600 actcagccgc ctgctggaca tggctgacgt ggccgtgtat ggtgtcgaggtgccaggaac 660 cgagggccgg gccggaatgg ctgctgtggc cagccccact ggcaactgtgacctgggagc 720 gctttgctca ggtc 734 <210> SEQ ID NO 17 <211> LENGTH: 213<212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 17 Ile GlyGlu Leu Cys Arg Tyr Leu Leu Asn Gln Pro Pro Arg Glu Ala 1 5 10 15 GluAsn Gln His Gln Val Arg Met Ala Leu Gly Asn Gly Leu Arg Gln 20 25 30 SerIle Trp Thr Asn Phe Ser Ser Arg Phe His Ile Pro Gln Val Ala 35 40 45 GluPhe Tyr Gly Ala Thr Glu Cys Asn Cys Ser Leu Gly Asn Phe Asp 50 55 60 SerGln Val Gly Ala Cys Gly Phe Asn Ser Arg Ile Leu Ser Phe Val 65 70 75 80Tyr Pro Ile Arg Leu Val Arg Val Asn Glu Asp Thr Met Glu Leu Ile 85 90 95Arg Gly Pro Asp Gly Val Cys Ile Pro Cys Gln Pro Gly Glu Pro Gly 100 105110 Gln Leu Val Gly Arg Ile Ile Gln Lys Asp Pro Leu Arg Arg Phe Asp 115120 125 Gly Tyr Leu Asn Gln Gly Ala Asn Asn Lys Lys Ile Ala Lys Asp Val130 135 140 Phe Lys Lys Gly Asp Gln Ala Tyr Leu Thr Gly Asp Val Leu ValMet 145 150 155 160 Asp Glu Leu Gly Tyr Leu Tyr Phe Arg Asp Arg Thr GlyAsp Thr Phe 165 170 175 Arg Trp Lys Gly Glu Asn Val Ser Thr Thr Glu ValGlu Gly Thr Leu 180 185 190 Ser Arg Leu Leu Asp Met Ala Asp Val Ala ValTyr Gly Val Glu Val 195 200 205 Pro Gly Thr Glu Gly 210 <210> SEQ ID NO18 <211> LENGTH: 1278 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220>FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(1278) <223>OTHER INFORMATION: n = A,T,C or G <220> FEATURE: <221> NAME/KEY:misc_feature <222> LOCATION: 2, 165, 292 <223> OTHER INFORMATION: n =A,T,C or G <400> SEQUENCE: 18 cntgcctctt gtaccacgtg atgggactttgtcgttggga tcctcggctg cttagatctc 60 ggagccacct gtgttctggc ccccaagttctctacttcct gcttctggga tgactgtcgg 120 cagcatggcg tgacagtgat cctgtatgtgggcgagctcc tgcgntactt gtgtaacatt 180 ccccagcaac cagaggaccg gacacatacagtccgcctgg caatgggcaa tggactacgg 240 gctgatgtgt ggggagacct tccagcagcgtttcggtcct atttcggatc tngggaagtc 300 ttacgggcty ccacagaagg gcaacatggggctttagttc aactattgtt gggggcgctg 360 cggggscctg grggcaaaga tggagcttgcctcctccgaa tgctgtcccc ctttgagctg 420 gtgcagttcg acatggaggc ggcggagcctgtgagggaca atcagggctt ctgcatccct 480 gtagggctag gggagccggg gctgctgttgaccaaggtgg taagccagca acccttcgtg 540 ggctaccgcg gcccccgaga gctgtcggaacggaagctgg tgcgcaacgt gcggcaatcg 600 ggcgacgttt actacaacac cggggacgtactggccatgg accgcgaagg cttcctctac 660 ttccgcgacc gactcgggga caccttccgatggaagggcg agaacgtgtc cacgcacgag 720 gtggagggcg tgttgtcgca ggtggacttcttgcaacagg ttaacgtgta tggcgtgtgc 780 gtgccaggtt gtgagggtaa ggtgggcatggctgctgtgg cattagcccc cggccagact 840 ttcgacgggg agaagttgta ccagcacgttcgcgcttggc tccctgccta cgctaccccc 900 catttcatcc gcatccagga cgccatggaggtcaccagca cgttcaaact gatgaagacc 960 cggttggtgc gtgagggctt caatgtggggatcgtggttg accctctgtt tgtactggac 1020 aaccgggccc agtccttccg gcccctgacggcagaaatgt accaggctgt gtgtgaggga 1080 acctggaggc tctgatcacc tggccaacccactggggtag ggatcaaagc cagccacccc 1140 caccccaaca cactcggtgt ccctttcatcctgggcctgt gtgaatccca gcctggccat 1200 accctcaacc tcagtgggct ggaaatgacagtgggccctg tagcagtggc agaataaact 1260 cagmtgygtt cacagaaa 1278 <210> SEQID NO 19 <211> LENGTH: 199 <212> TYPE: PRT <213> ORGANISM: Homo sapiens<400> SEQUENCE: 19 Glu Gly Gln His Gly Ala Leu Val Gln Leu Leu Leu GlyAla Leu Arg 1 5 10 15 Gly Pro Gly Gly Lys Asp Gly Ala Cys Leu Leu ArgMet Leu Ser Pro 20 25 30 Phe Glu Leu Val Gln Phe Asp Met Glu Ala Ala GluPro Val Arg Asp 35 40 45 Asn Gln Gly Phe Cys Ile Pro Val Gly Leu Gly GluPro Gly Leu Leu 50 55 60 Leu Thr Lys Val Val Ser Gln Gln Pro Phe Val GlyTyr Arg Gly Pro 65 70 75 80 Arg Glu Leu Ser Glu Arg Lys Leu Val Arg AsnVal Arg Gln Ser Gly 85 90 95 Asp Val Tyr Tyr Asn Thr Gly Asp Val Leu AlaMet Asp Arg Glu Gly 100 105 110 Phe Leu Tyr Phe Arg Asp Arg Leu Gly AspThr Phe Arg Trp Lys Gly 115 120 125 Glu Asn Val Ser Thr His Glu Val GluGly Val Leu Ser Gln Val Asp 130 135 140 Phe Leu Gln Gln Val Asn Val TyrGly Val Cys Val Pro Gly Cys Glu 145 150 155 160 Gly Lys Val Gly Met AlaAla Val Ala Leu Ala Pro Gly Gln Thr Phe 165 170 175 Asp Gly Glu Lys LeuTyr Gln His Val Arg Ala Trp Leu Pro Ala Tyr 180 185 190 Ala Thr Pro HisPhe Ile Arg 195 <210> SEQ ID NO 20 <211> LENGTH: 1361 <212> TYPE: DNA<213> ORGANISM: Homo sapiens <400> SEQUENCE: 20 cgcttgtgtg ttaaagaagaaattttcagc aagccagttt tggagtgact gcaagaagta 60 tgatgtgact gtgtttcagtatattggaga actttgtcgc tacctttgca aacaatctaa 120 gagagaagga gaaaaggatcataaggtgcg tttggcaatt ggaaatggca tacggagtga 180 tgtatggaga gaatttttagacagatttgg aaatataaag gtgtgtgaac tttatgcagc 240 taccgaatca agcatatctttcatgaacta cactgggaga attggagcaa ttgggagaac 300 aaatttgttt tacaaacttctttccacttt tgacttaata aagtatgact ttcagaaaga 360 tgaacccatg agaaatgagcagggttgggt attcatgaga aaaaggagac ctggacttct 420 catttctcga gtgaatgcaaaaaatccctt ctttggctat gctgggcctt ataagcacac 480 aaaagacaaa ttgctttgtgatgtttttaa gaagggagat gtttacctta atactggaga 540 cttaatagtc caggatcaggacaatttcct ttatttttgg gaccgtactg gagacacttt 600 cagatggaaa ggagaaaatgtcgcaaccac tgaggttgct gatgttattg gaatgttgga 660 tttcatacag gaagcaaacgtctatggtgt ggctatatca ggttatgaag gaagagcagg 720 aatggcttct attattttaaaaccaaatac atctttagat ttggaaaaag tttatgaaca 780 agttgtaaca tttctaccagcttatgcttg tccacgattt ttaagaattc aggaaaaaat 840 ggaagcaaca ggaacattcaaactattgaa gcatcagttg gtggaagatg gatttaatcc 900 actgaaaatt tctgaaccactttacttcat ggataacttg aaaaagtctt atgttctact 960 gaccagggaa ctttatgatcaaataatgtt aggggaaata aaactttaag atttttatat 1020 ctagaacttt catatgctttcttaggaaga gtgagagggg ggtatatgat tctttatgaa 1080 atggggaaag ggagctaacattaattatgc atgtactata tttccttaat atgagagata 1140 attttttaat tgcataagaattttaatttc ttttaattga tataaacaga gttgattatt 1200 ctttttatct atttggagattcagtgcata actaagtatt ttccttaata ctaaagattt 1260 taaataataa atagtggctagcggtttgga caatcactaa aaatgtactt tctaataagt 1320 aaaatttcta attttgaataaaagattaaa ttttactgaa a 1361 <210> SEQ ID NO 21 <211> LENGTH: 335 <212>TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 21 Ala Cys ValLeu Lys Lys Lys Phe Ser Ala Ser Gln Phe Trp Ser Asp 1 5 10 15 Cys LysLys Tyr Asp Val Thr Val Phe Gln Tyr Ile Gly Glu Leu Cys 20 25 30 Arg TyrLeu Cys Lys Gln Ser Lys Arg Glu Gly Glu Lys Asp His Lys 35 40 45 Val ArgLeu Ala Ile Gly Asn Gly Ile Arg Ser Asp Val Trp Arg Glu 50 55 60 Phe LeuAsp Arg Phe Gly Asn Ile Lys Val Cys Glu Leu Tyr Ala Ala 65 70 75 80 ThrGlu Ser Ser Ile Ser Phe Met Asn Tyr Thr Gly Arg Ile Gly Ala 85 90 95 IleGly Arg Thr Asn Leu Phe Tyr Lys Leu Leu Ser Thr Phe Asp Leu 100 105 110Ile Lys Tyr Asp Phe Gln Lys Asp Glu Pro Met Arg Asn Glu Gln Gly 115 120125 Trp Val Phe Met Arg Lys Arg Arg Pro Gly Leu Leu Ile Ser Arg Val 130135 140 Asn Ala Lys Asn Pro Phe Phe Gly Tyr Ala Gly Pro Tyr Lys His Thr145 150 155 160 Lys Asp Lys Leu Leu Cys Asp Val Phe Lys Lys Gly Asp ValTyr Leu 165 170 175 Asn Thr Gly Asp Leu Ile Val Gln Asp Gln Asp Asn PheLeu Tyr Phe 180 185 190 Trp Asp Arg Thr Gly Asp Thr Phe Arg Trp Lys GlyGlu Asn Val Ala 195 200 205 Thr Thr Glu Val Ala Asp Val Ile Gly Met LeuAsp Phe Ile Gln Glu 210 215 220 Ala Asn Val Tyr Gly Val Ala Ile Ser GlyTyr Glu Gly Arg Ala Gly 225 230 235 240 Met Ala Ser Ile Ile Leu Lys ProAsn Thr Ser Leu Asp Leu Glu Lys 245 250 255 Val Tyr Glu Gln Val Val ThrPhe Leu Pro Ala Tyr Ala Cys Pro Arg 260 265 270 Phe Leu Arg Ile Gln GluLys Met Glu Ala Thr Gly Thr Phe Lys Leu 275 280 285 Leu Lys His Gln LeuVal Glu Asp Gly Phe Asn Pro Leu Lys Ile Ser 290 295 300 Glu Pro Leu TyrPhe Met Asp Asn Leu Lys Lys Ser Tyr Val Leu Leu 305 310 315 320 Thr ArgGlu Leu Tyr Asp Gln Ile Met Leu Gly Glu Ile Lys Leu 325 330 335 <210>SEQ ID NO 22 <211> LENGTH: 2007 <212> TYPE: DNA <213> ORGANISM:Mycobacterium tuberculosis <400> SEQUENCE: 22 tagtcgataa cgtcaaggacgctctgcggg cctgcgcacc ttcctgaggt tggtcgacaa 60 ccaattcgac atttcgcaaacgaatcgagg gcttacgtgt ccgattacta cggcggcgca 120 cacacaacgg tcaggctgatcgacctggca actcggatgc cgcgagtgtt ggcggacacg 180 ccggtgattg tgcgtggggcaatgaccggg ctgctggccc ggccgaattc caaggcgtcg 240 atcggcacgg tgttccaggaccgggccgct cgctacggtg accgagtctt cctgaaattc 300 ggcgatcagc agctgacctaccgcgacgct aacgccaccg ccaaccggta cgccgcggtg 360 ttggccgccc gcggcgtcggccccggcgac gtcgttggca tcatgttgcg taactcaccc 420 agcacagtct tggcgatgctggccacggtc aagtgcggcg ctatcgccgg catgctcaac 480 taccaccagc gcggcgaggtgttggcgcac agcctgggtc tgctggacgc gaaggtactg 540 atcgcagagt ccgacttggtcagcgccgtc gccgaatgcg gcgcctcgcg cggccgggta 600 gcgggcgacg tgctgaccgtcgaggacgtg gagcgattcg ccacaacggc gcccgccacc 660 aacccggcgt cggcgtcggcggtgcaagcc aaagacaccg cgttctacat cttcacctcg 720 ggcaccaccg gatttcccaaggccagtgtc atgacgcatc atcggtggct gcgggcgctg 780 gccgtcttcg gagggatggggctgcggctg aagggttccg acacgctcta cagctgcctg 840 ccgctgtacc acaacaacgcgttaacggtc gcggtgtcgt cggtgatcaa ttctggggcg 900 accctggcgc tgggtaagtcgttttcggcg tcgcggttct gggatgaggt gattgccaac 960 cgggcgacgg cgttcgtctacatcggcgaa atctgccgtt atctgctcaa ccagccggcc 1020 aagccgaccg accgtgcccaccaggtgcgg gtgatctgcg gtaacgggct gcggccggag 1080 atctgggatg agttcaccacccgcttcggg gtcgcgcggg tgtgcgagtt ctacgccgcc 1140 agcgaaggca actcggcctttatcaacatc ttcaacgtgc ccaggaccgc cggggtatcg 1200 ccgatgccgc ttgcctttgtggaatacgac ctggacaccg gcgatccgct gcgggatgcg 1260 agcgggcgag tgcgtcgggtacccgacggt gaacccggcc tgttgcttag ccgggtcaac 1320 cggctgcagc cgttcgacggctacaccgac ccggttgcca gcgaaaagaa gttggtgcgc 1380 aacgcttttc gagatggcgactgttggttc aacaccggtg acgtgatgag cccgcagggc 1440 atgggccatg ccgccttcgtcgatcggctg ggcgacacct tccgctggaa gggcgagaat 1500 gtcgccacca ctcaggtcgaagcggcactg gcctccgacc agaccgtcga ggagtgcacg 1560 gtctacggcg tccagattccgcgcaccggc gggcgcgccg gaatggccgc gatcacactg 1620 cgcgctggcg ccgaattcgacggccaggcg ctggcccgaa cggtttacgg tcacttgccc 1680 ggctatgcac ttccgctctttgttcgggta gtggggtcgc tggcgcacac cacgacgttc 1740 aagagtcgca aggtggagttgcgcaaccag gcctatggcg ccgacatcga ggatccgctg 1800 tacgtactgg ccggcccggacgaaggatat gtgccgtact acgccgaata ccctgaggag 1860 gtttcgctcg gaaggcgaccgcagggctag cggattccgg gcgcagtctc gatacccgca 1920 ctggacgctc gacggtaaccaggcactatg gatgcgtgcg ttcaacaccg ccggcctcag 1980 ccggtcgttc aacaccgccggcgttag 2007 <210> SEQ ID NO 23 <211> LENGTH: 597 <212> TYPE: PRT <213>ORGANISM: Mycobacterium tuberculosis <400> SEQUENCE: 23 Met Ser Asp TyrTyr Gly Gly Ala His Thr Thr Val Arg Leu Ile Asp 1 5 10 15 Leu Ala ThrArg Met Pro Arg Val Leu Ala Asp Thr Pro Val Ile Val 20 25 30 Arg Gly AlaMet Thr Gly Leu Leu Ala Arg Pro Asn Ser Lys Ala Ser 35 40 45 Ile Gly ThrVal Phe Gln Asp Arg Ala Ala Arg Tyr Gly Asp Arg Val 50 55 60 Phe Leu LysPhe Gly Asp Gln Gln Leu Thr Tyr Arg Asp Ala Asn Ala 65 70 75 80 Thr AlaAsn Arg Tyr Ala Ala Val Leu Ala Ala Arg Gly Val Gly Pro 85 90 95 Gly AspVal Val Gly Ile Met Leu Arg Asn Ser Pro Ser Thr Val Leu 100 105 110 AlaMet Leu Ala Thr Val Lys Cys Gly Ala Ile Ala Gly Met Leu Asn 115 120 125Tyr His Gln Arg Gly Glu Val Leu Ala His Ser Leu Gly Leu Leu Asp 130 135140 Ala Lys Val Leu Ile Ala Glu Ser Asp Leu Val Ser Ala Val Ala Glu 145150 155 160 Cys Gly Ala Ser Arg Gly Arg Val Ala Gly Asp Val Leu Thr ValGlu 165 170 175 Asp Val Glu Arg Phe Ala Thr Thr Ala Pro Ala Thr Asn ProAla Ser 180 185 190 Ala Ser Ala Val Gln Ala Lys Asp Thr Ala Phe Tyr IlePhe Thr Ser 195 200 205 Gly Thr Thr Gly Phe Pro Lys Ala Ser Val Met ThrHis His Arg Trp 210 215 220 Leu Arg Ala Leu Ala Val Phe Gly Gly Met GlyLeu Arg Leu Lys Gly 225 230 235 240 Ser Asp Thr Leu Tyr Ser Cys Leu ProLeu Tyr His Asn Asn Ala Leu 245 250 255 Thr Val Ala Val Ser Ser Val IleAsn Ser Gly Ala Thr Leu Ala Leu 260 265 270 Gly Lys Ser Phe Ser Ala SerArg Phe Trp Asp Glu Val Ile Ala Asn 275 280 285 Arg Ala Thr Ala Phe ValTyr Ile Gly Glu Ile Cys Arg Tyr Leu Leu 290 295 300 Asn Gln Pro Ala LysPro Thr Asp Arg Ala His Gln Val Arg Val Ile 305 310 315 320 Cys Gly AsnGly Leu Arg Pro Glu Ile Trp Asp Glu Phe Thr Thr Arg 325 330 335 Phe GlyVal Ala Arg Val Cys Glu Phe Tyr Ala Ala Ser Glu Gly Asn 340 345 350 SerAla Phe Ile Asn Ile Phe Asn Val Pro Arg Thr Ala Gly Val Ser 355 360 365Pro Met Pro Leu Ala Phe Val Glu Tyr Asp Leu Asp Thr Gly Asp Pro 370 375380 Leu Arg Asp Ala Ser Gly Arg Val Arg Arg Val Pro Asp Gly Glu Pro 385390 395 400 Gly Leu Leu Leu Ser Arg Val Asn Arg Leu Gln Pro Phe Asp GlyTyr 405 410 415 Thr Asp Pro Val Ala Ser Glu Lys Lys Leu Val Arg Asn AlaPhe Arg 420 425 430 Asp Gly Asp Cys Trp Phe Asn Thr Gly Asp Val Met SerPro Gln Gly 435 440 445 Met Gly His Ala Ala Phe Val Asp Arg Leu Gly AspThr Phe Arg Trp 450 455 460 Lys Gly Glu Asn Val Ala Thr Thr Gln Val GluAla Ala Leu Ala Ser 465 470 475 480 Asp Gln Thr Val Glu Glu Cys Thr ValTyr Gly Val Gln Ile Pro Arg 485 490 495 Thr Gly Gly Arg Ala Gly Met AlaAla Ile Thr Leu Arg Ala Gly Ala 500 505 510 Glu Phe Asp Gly Gln Ala LeuAla Arg Thr Val Tyr Gly His Leu Pro 515 520 525 Gly Tyr Ala Leu Pro LeuPhe Val Arg Val Val Gly Ser Leu Ala His 530 535 540 Thr Thr Thr Phe LysSer Arg Lys Val Glu Leu Arg Asn Gln Ala Tyr 545 550 555 560 Gly Ala AspIle Glu Asp Pro Leu Tyr Val Leu Ala Gly Pro Asp Glu 565 570 575 Gly TyrVal Pro Tyr Tyr Ala Glu Tyr Pro Glu Glu Val Ser Leu Gly 580 585 590 ArgArg Pro Gln Gly 595 <210> SEQ ID NO 24 <211> LENGTH: 3704 <212> TYPE:DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: CDS<222> LOCATION: (175)...(2112) <400> SEQUENCE: 24 tcgacccacg gcgtccgggaccccaaagca gaagcccgca cagtaggcac agcgcaccca 60 agaagggtcc aggagtctgcagaaacagaa aggtccccgg cctcagcctc ctagtccctg 120 cctgcctcct gcctgagcttctgggagact gaaggcacgg cttgcagctt cagg atg 177 Met 1 cgg gct ccg ggt gcgggc gcg gcc tcg gtg gtc tcg ctg gcg ctg ttg 225 Arg Ala Pro Gly Ala GlyAla Ala Ser Val Val Ser Leu Ala Leu Leu 5 10 15 tgg ctg ctg ggg ctg ccgtgg acc tgg agc gcg gca gcg gcg ctc ggc 273 Trp Leu Leu Gly Leu Pro TrpThr Trp Ser Ala Ala Ala Ala Leu Gly 20 25 30 gtg tac gtg ggc agc ggc ggctgg cgc ttc ctg cgc atc gtc tgc aag 321 Val Tyr Val Gly Ser Gly Gly TrpArg Phe Leu Arg Ile Val Cys Lys 35 40 45 acc gcg agg cga gac ctc ttc ggtctc tct gtg ctg atc cgc gtg cgc 369 Thr Ala Arg Arg Asp Leu Phe Gly LeuSer Val Leu Ile Arg Val Arg 50 55 60 65 ctg gag ctg cgg cgg cac cag cgtgcc ggc cac acc atc ccg cgc atc 417 Leu Glu Leu Arg Arg His Gln Arg AlaGly His Thr Ile Pro Arg Ile 70 75 80 ttt cag gcg gta gtg cag cga cag cccgag cgc ctg gcg ctg gtg gat 465 Phe Gln Ala Val Val Gln Arg Gln Pro GluArg Leu Ala Leu Val Asp 85 90 95 gcc ggg acc ggc gag tgc tgg acc ttt gcgcag ctg gac gcc tac tcc 513 Ala Gly Thr Gly Glu Cys Trp Thr Phe Ala GlnLeu Asp Ala Tyr Ser 100 105 110 aat gcg gta gcc aac ctc ttc cgc cag ctgggc ttc gcg ccg ggc gac 561 Asn Ala Val Ala Asn Leu Phe Arg Gln Leu GlyPhe Ala Pro Gly Asp 115 120 125 gtg gtg gcc atc ttc ctg gag ggc cgg ccggag ttc gtg ggg ctg tgg 609 Val Val Ala Ile Phe Leu Glu Gly Arg Pro GluPhe Val Gly Leu Trp 130 135 140 145 ctg ggc ctg gcc aag gcg ggc atg gaggcc gcg ctg ctc aac gtg aac 657 Leu Gly Leu Ala Lys Ala Gly Met Glu AlaAla Leu Leu Asn Val Asn 150 155 160 ctg cgg cgc gag ccc ctg gcc ttc tgcctg ggc acc tcg ggc gct aag 705 Leu Arg Arg Glu Pro Leu Ala Phe Cys LeuGly Thr Ser Gly Ala Lys 165 170 175 gcc ctg atc ttt gga gga gaa atg gtggcg gcg gtg gcc gaa gtg agc 753 Ala Leu Ile Phe Gly Gly Glu Met Val AlaAla Val Ala Glu Val Ser 180 185 190 ggg cat ctg ggg aaa agt ttg atc aagttc tgc tct gga gac ttg ggg 801 Gly His Leu Gly Lys Ser Leu Ile Lys PheCys Ser Gly Asp Leu Gly 195 200 205 ccc gag ggc atc ttg ccg gac acc cacctc ctg gac ccg ctg ctg aag 849 Pro Glu Gly Ile Leu Pro Asp Thr His LeuLeu Asp Pro Leu Leu Lys 210 215 220 225 gag gcc tct act gcc ccc ttg gcacag atc ccc agc aag ggc atg gac 897 Glu Ala Ser Thr Ala Pro Leu Ala GlnIle Pro Ser Lys Gly Met Asp 230 235 240 gat cgt ctt ttc tac atc tac acgtcg ggg acc acc ggg ctg ccc aag 945 Asp Arg Leu Phe Tyr Ile Tyr Thr SerGly Thr Thr Gly Leu Pro Lys 245 250 255 gct gcc att gtc gtg cac agc aggtac tac cgc atg gca gcc ttc ggc 993 Ala Ala Ile Val Val His Ser Arg TyrTyr Arg Met Ala Ala Phe Gly 260 265 270 cac cac gcc tac cgc atg cag gcggct gac gtg ctc tat gac tgc ctg 1041 His His Ala Tyr Arg Met Gln Ala AlaAsp Val Leu Tyr Asp Cys Leu 275 280 285 ccc ctg tac cac tcg gca gga aacatc atc ggc gtg ggg cag tgt ctc 1089 Pro Leu Tyr His Ser Ala Gly Asn IleIle Gly Val Gly Gln Cys Leu 290 295 300 305 atc tat ggg ctg aca gtc gtcctc cgc aag aaa ttc tcg gcc agc cgc 1137 Ile Tyr Gly Leu Thr Val Val LeuArg Lys Lys Phe Ser Ala Ser Arg 310 315 320 ttc tgg gac gac tgc atc aagtac aac tgc acg gtg gtt cag tac atc 1185 Phe Trp Asp Asp Cys Ile Lys TyrAsn Cys Thr Val Val Gln Tyr Ile 325 330 335 ggg gag atc tgc cgc tac ctgctg aag cag ccg gtg cgc gag gcg gag 1233 Gly Glu Ile Cys Arg Tyr Leu LeuLys Gln Pro Val Arg Glu Ala Glu 340 345 350 agg cga cac cgc gtg cgc ctggcg gtg ggg aac ggg ctg cgt cct gcc 1281 Arg Arg His Arg Val Arg Leu AlaVal Gly Asn Gly Leu Arg Pro Ala 355 360 365 atc tgg gag gag ttc acg gagcgc ttc ggc gta cgc caa atc ggg gag 1329 Ile Trp Glu Glu Phe Thr Glu ArgPhe Gly Val Arg Gln Ile Gly Glu 370 375 380 385 ttc tac ggc gcc acc gagtgc aac tgc agc att gcc aac atg gac ggc 1377 Phe Tyr Gly Ala Thr Glu CysAsn Cys Ser Ile Ala Asn Met Asp Gly 390 395 400 aag gtc ggc tcc tgt ggtttc aac agc cgc atc ctg ccc cac gtg tac 1425 Lys Val Gly Ser Cys Gly PheAsn Ser Arg Ile Leu Pro His Val Tyr 405 410 415 ccc atc cgg ctg gtg aaggtc aat gag gac aca atg gag ctg ctg cgg 1473 Pro Ile Arg Leu Val Lys ValAsn Glu Asp Thr Met Glu Leu Leu Arg 420 425 430 gat gcc cag ggc ctc tgcatc ccc tgc cag gcc ggg gag cct ggc ctc 1521 Asp Ala Gln Gly Leu Cys IlePro Cys Gln Ala Gly Glu Pro Gly Leu 435 440 445 ctt gtg ggt cag atc aaccaa cag gac ccg ctg cgc cgc ttc gat ggc 1569 Leu Val Gly Gln Ile Asn GlnGln Asp Pro Leu Arg Arg Phe Asp Gly 450 455 460 465 tat gtc agc gag agcgcc acc agc aag aag atc gcc cac agc gtc ttc 1617 Tyr Val Ser Glu Ser AlaThr Ser Lys Lys Ile Ala His Ser Val Phe 470 475 480 agc aag ggc gac agcgcc tac ctc tca ggt gac gtg cta gtg atg gat 1665 Ser Lys Gly Asp Ser AlaTyr Leu Ser Gly Asp Val Leu Val Met Asp 485 490 495 gag ctg ggc tac atgtac ttc cgg gac cgt agc ggg gac acc ttc cgc 1713 Glu Leu Gly Tyr Met TyrPhe Arg Asp Arg Ser Gly Asp Thr Phe Arg 500 505 510 tgg cga ggg gag aacgtc tcc acc acc gag gtg gag ggc gtg ctg agc 1761 Trp Arg Gly Glu Asn ValSer Thr Thr Glu Val Glu Gly Val Leu Ser 515 520 525 cgc ctg ctg ggc cagaca gac gtg gcc gtc tat ggg gtg gct gtt cca 1809 Arg Leu Leu Gly Gln ThrAsp Val Ala Val Tyr Gly Val Ala Val Pro 530 535 540 545 gga gtg gag ggtaag gca ggg atg gcg gcc gtc gca gac ccc cac agc 1857 Gly Val Glu Gly LysAla Gly Met Ala Ala Val Ala Asp Pro His Ser 550 555 560 ctg ctg gac cccaac gcg ata tac cag gag ctg cag aag gtg ctg gca 1905 Leu Leu Asp Pro AsnAla Ile Tyr Gln Glu Leu Gln Lys Val Leu Ala 565 570 575 ccc tat gcc cggccc atc ttc ctg cgc ctc ctg ccc cag gtg gac acc 1953 Pro Tyr Ala Arg ProIle Phe Leu Arg Leu Leu Pro Gln Val Asp Thr 580 585 590 aca ggc acc ttcaag atc cag aag acg agg ctg cag cga gag ggc ttt 2001 Thr Gly Thr Phe LysIle Gln Lys Thr Arg Leu Gln Arg Glu Gly Phe 595 600 605 gac cca cgc cagacc tca gac cgg ctc ttc ttc ctg gac ctg aag cag 2049 Asp Pro Arg Gln ThrSer Asp Arg Leu Phe Phe Leu Asp Leu Lys Gln 610 615 620 625 ggc cac tacctg ccc tta aat gag gca gtc tac act cgc atc tgc tcg 2097 Gly His Tyr LeuPro Leu Asn Glu Ala Val Tyr Thr Arg Ile Cys Ser 630 635 640 ggc gcc ttcgcc ctc tgaagctgtt cctctactgg ccacaaactc tgggcctggt 2152 Gly Ala Phe AlaLeu 645 gggagaggcc agcttgagcc agacagcgct gcccaggggt ggccgcctagtacacaccca 2212 cctggccgag ctgtacctgg cacggcccat cctggactga gaaactggaacctcagagga 2272 acccgtgcct ctctgctgcc ttggtgcccc tgtgtctgcc tcctctccctgcttttcagc 2332 ctctgtctcc ttccatccct gtccctgtct ggccttaact cttccctctctttcttttct 2392 ttctttcttt cttttttttt aagatagagt ctcactctgc tgcccgggctagagtgcagt 2452 ggtgggatct cggctcactg caacctctgc ctcctggggt tcaagtgatcctcccacctc 2512 agcctcctga gtagctggga ttacaggcac ccgccaccac gtccagctaatttttatatt 2572 tttagtagag acggggtttc accatgttgg tcaggctggt cttgaactcctgacctcagg 2632 tgatccgctg gcctcggcct cccagagtgc tgggattata ggcgtgagcctctggcccgg 2692 cctttccttt ttcctctcct ctcctgccga gagtggaaca cacgtgtcctgggagctgca 2752 tcttgtgtag ggtccagctg cttttgggga ctgcaggaat catctcccctgggccctgga 2812 ctcggactgg ggcctcccca cctccctctc ggctgtgcct tacggagccccaatccaggc 2872 ctcctgtggc tgttgggttc cagatgctgc agctccatgt gacttccaagcaggccctcc 2932 gccctccctg ctgaatggag gagccggggg tcccccaggc caactggaaaatctcccagg 2992 ctaggccaat tgccttttgc acttccccgt tcctgtcaca tttccccagccccaccttcc 3052 cctcctgatg ccctgaaagc ttccggaatt gactgtgacc acttggatgtcaccactgtc 3112 agcccctgcc ttgatgtccc catttagcca tctccatgga gctcctgctggagggccctg 3172 aaccctgcac tgcgtggctg cccagccagc tgcctcctgt cctgggaggaggcctcctgg 3232 gtgtcctcat ctggtgtgtc tactggaggg tcccacagga gaggcagcagaggggtcagg 3292 ggaggtctcc tgccgggggt tggcctctca agcctcaggg gttctagcctgttgaatata 3352 ccccacctgg tgggtggccc ctccgatgtc cccactgatg gctctgacaccgtgttggtg 3412 gcgatgtccc agacaatccc accaggacgg cccagacatc cctactggcttcgctggtgg 3472 ctcatctcga acatccacgc cagcctttct ggggccggcc acccaggccgcctgtccgtc 3532 tgtcctccct ccagcagcac cccctggccc ctggagtggt ggggccatggcaagagacac 3592 cgtggcgtct catgtgaact ttcctgggca ctgtggtttt atttcctaattgatttaaga 3652 aataaacctg aagaccgtct ggtgaaaaaa aaaaaaaaaa aagggcggccgc 3704 <210> SEQ ID NO 25 <211> LENGTH: 646 <212> TYPE: PRT <213>ORGANISM: Homo sapiens <400> SEQUENCE: 25 Met Arg Ala Pro Gly Ala GlyAla Ala Ser Val Val Ser Leu Ala Leu 1 5 10 15 Leu Trp Leu Leu Gly LeuPro Trp Thr Trp Ser Ala Ala Ala Ala Leu 20 25 30 Gly Val Tyr Val Gly SerGly Gly Trp Arg Phe Leu Arg Ile Val Cys 35 40 45 Lys Thr Ala Arg Arg AspLeu Phe Gly Leu Ser Val Leu Ile Arg Val 50 55 60 Arg Leu Glu Leu Arg ArgHis Gln Arg Ala Gly His Thr Ile Pro Arg 65 70 75 80 Ile Phe Gln Ala ValVal Gln Arg Gln Pro Glu Arg Leu Ala Leu Val 85 90 95 Asp Ala Gly Thr GlyGlu Cys Trp Thr Phe Ala Gln Leu Asp Ala Tyr 100 105 110 Ser Asn Ala ValAla Asn Leu Phe Arg Gln Leu Gly Phe Ala Pro Gly 115 120 125 Asp Val ValAla Ile Phe Leu Glu Gly Arg Pro Glu Phe Val Gly Leu 130 135 140 Trp LeuGly Leu Ala Lys Ala Gly Met Glu Ala Ala Leu Leu Asn Val 145 150 155 160Asn Leu Arg Arg Glu Pro Leu Ala Phe Cys Leu Gly Thr Ser Gly Ala 165 170175 Lys Ala Leu Ile Phe Gly Gly Glu Met Val Ala Ala Val Ala Glu Val 180185 190 Ser Gly His Leu Gly Lys Ser Leu Ile Lys Phe Cys Ser Gly Asp Leu195 200 205 Gly Pro Glu Gly Ile Leu Pro Asp Thr His Leu Leu Asp Pro LeuLeu 210 215 220 Lys Glu Ala Ser Thr Ala Pro Leu Ala Gln Ile Pro Ser LysGly Met 225 230 235 240 Asp Asp Arg Leu Phe Tyr Ile Tyr Thr Ser Gly ThrThr Gly Leu Pro 245 250 255 Lys Ala Ala Ile Val Val His Ser Arg Tyr TyrArg Met Ala Ala Phe 260 265 270 Gly His His Ala Tyr Arg Met Gln Ala AlaAsp Val Leu Tyr Asp Cys 275 280 285 Leu Pro Leu Tyr His Ser Ala Gly AsnIle Ile Gly Val Gly Gln Cys 290 295 300 Leu Ile Tyr Gly Leu Thr Val ValLeu Arg Lys Lys Phe Ser Ala Ser 305 310 315 320 Arg Phe Trp Asp Asp CysIle Lys Tyr Asn Cys Thr Val Val Gln Tyr 325 330 335 Ile Gly Glu Ile CysArg Tyr Leu Leu Lys Gln Pro Val Arg Glu Ala 340 345 350 Glu Arg Arg HisArg Val Arg Leu Ala Val Gly Asn Gly Leu Arg Pro 355 360 365 Ala Ile TrpGlu Glu Phe Thr Glu Arg Phe Gly Val Arg Gln Ile Gly 370 375 380 Glu PheTyr Gly Ala Thr Glu Cys Asn Cys Ser Ile Ala Asn Met Asp 385 390 395 400Gly Lys Val Gly Ser Cys Gly Phe Asn Ser Arg Ile Leu Pro His Val 405 410415 Tyr Pro Ile Arg Leu Val Lys Val Asn Glu Asp Thr Met Glu Leu Leu 420425 430 Arg Asp Ala Gln Gly Leu Cys Ile Pro Cys Gln Ala Gly Glu Pro Gly435 440 445 Leu Leu Val Gly Gln Ile Asn Gln Gln Asp Pro Leu Arg Arg PheAsp 450 455 460 Gly Tyr Val Ser Glu Ser Ala Thr Ser Lys Lys Ile Ala HisSer Val 465 470 475 480 Phe Ser Lys Gly Asp Ser Ala Tyr Leu Ser Gly AspVal Leu Val Met 485 490 495 Asp Glu Leu Gly Tyr Met Tyr Phe Arg Asp ArgSer Gly Asp Thr Phe 500 505 510 Arg Trp Arg Gly Glu Asn Val Ser Thr ThrGlu Val Glu Gly Val Leu 515 520 525 Ser Arg Leu Leu Gly Gln Thr Asp ValAla Val Tyr Gly Val Ala Val 530 535 540 Pro Gly Val Glu Gly Lys Ala GlyMet Ala Ala Val Ala Asp Pro His 545 550 555 560 Ser Leu Leu Asp Pro AsnAla Ile Tyr Gln Glu Leu Gln Lys Val Leu 565 570 575 Ala Pro Tyr Ala ArgPro Ile Phe Leu Arg Leu Leu Pro Gln Val Asp 580 585 590 Thr Thr Gly ThrPhe Lys Ile Gln Lys Thr Arg Leu Gln Arg Glu Gly 595 600 605 Phe Asp ProArg Gln Thr Ser Asp Arg Leu Phe Phe Leu Asp Leu Lys 610 615 620 Gln GlyHis Tyr Leu Pro Leu Asn Glu Ala Val Tyr Thr Arg Ile Cys 625 630 635 640Ser Gly Ala Phe Ala Leu 645 <210> SEQ ID NO 26 <211> LENGTH: 2917 <212>TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY:CDS <222> LOCATION: (208)...(2136) <400> SEQUENCE: 26 cgacccacgcgtccgggcgg gcggggccgg gcggcgggcg gggctggcgg ggcggccggg 60 ccatgcagggcgcagagccg gctaaaccct gctgagaccc ggctccgtgc gtccaggggc 120 ggctaatgcccctcacgctg tctacgctgc tgcaaccggg ccgcatctgg acggggcgcc 180 gcgcggcggagccgacgccg ggccaca atg ctg ctt gga gcc tct ctg gtg ggg 234 Met Leu LeuGly Ala Ser Leu Val Gly 1 5 gtg ctg ctg ttc tcc aag ctg gtg ctg aaa ctgccc tgg acc cag gtg 282 Val Leu Leu Phe Ser Lys Leu Val Leu Lys Leu ProTrp Thr Gln Val 10 15 20 25 gga ttc tcc ctg ttg ttc ctc tac ttg gga tctggc ggc tgg cgc ttc 330 Gly Phe Ser Leu Leu Phe Leu Tyr Leu Gly Ser GlyGly Trp Arg Phe 30 35 40 atc cgg gtc ttc atc aag acc atc agg cgc gat atcttt ggc ggc ctg 378 Ile Arg Val Phe Ile Lys Thr Ile Arg Arg Asp Ile PheGly Gly Leu 45 50 55 gtc ctc ctg aag gtg aag gca aag gtg cga cag tgc ctgcag gag cgg 426 Val Leu Leu Lys Val Lys Ala Lys Val Arg Gln Cys Leu GlnGlu Arg 60 65 70 cgg aca gtg ccc att ttg ttt gcc tct acc gtt cgg cgc cacccc gac 474 Arg Thr Val Pro Ile Leu Phe Ala Ser Thr Val Arg Arg His ProAsp 75 80 85 aag acg gcc ctg atc ttc gag ggc aca gat acc cac tgg acc ttccgc 522 Lys Thr Ala Leu Ile Phe Glu Gly Thr Asp Thr His Trp Thr Phe Arg90 95 100 105 cag ctg gat gag tac tca agc agt gta gcc aac ttc ctg caggcc cgg 570 Gln Leu Asp Glu Tyr Ser Ser Ser Val Ala Asn Phe Leu Gln AlaArg 110 115 120 ggc ctg gcc tcg ggc gat gtg gct gcc atc ttc atg gag aaccgc aat 618 Gly Leu Ala Ser Gly Asp Val Ala Ala Ile Phe Met Glu Asn ArgAsn 125 130 135 gag ttc gtg ggc cta tgg ctg ggc atg gcc aag ctc ggt gtggag gca 666 Glu Phe Val Gly Leu Trp Leu Gly Met Ala Lys Leu Gly Val GluAla 140 145 150 gcc ctc atc aac acc aac ctg cgg cgg gat gct ctg ctc cactgc ctc 714 Ala Leu Ile Asn Thr Asn Leu Arg Arg Asp Ala Leu Leu His CysLeu 155 160 165 acc acc tcg cgc gca cgg gcc ctt gtc ttt ggc agc gaa atggcc tca 762 Thr Thr Ser Arg Ala Arg Ala Leu Val Phe Gly Ser Glu Met AlaSer 170 175 180 185 gcc atc tgt gag gtc cat gcc agc ctg gac ccc tcg ctcagc ctc ttc 810 Ala Ile Cys Glu Val His Ala Ser Leu Asp Pro Ser Leu SerLeu Phe 190 195 200 tgc tct ggc tcc tgg gag ccc ggt gcg gtg cct cca agcaca gaa cac 858 Cys Ser Gly Ser Trp Glu Pro Gly Ala Val Pro Pro Ser ThrGlu His 205 210 215 ctg gac cct ctg ctg aaa gat gct ccc aag cac ctt cccagt tgc cct 906 Leu Asp Pro Leu Leu Lys Asp Ala Pro Lys His Leu Pro SerCys Pro 220 225 230 gac aag ggc ttc aca gat aaa ctg ttc tac atc tac acatcc ggc acc 954 Asp Lys Gly Phe Thr Asp Lys Leu Phe Tyr Ile Tyr Thr SerGly Thr 235 240 245 aca ggg ctg ccc aag gcc gcc atc gtg gtg cac agc aggtat tac cgc 1002 Thr Gly Leu Pro Lys Ala Ala Ile Val Val His Ser Arg TyrTyr Arg 250 255 260 265 atg gct gcc ctg gtg tac tat gga ttc cgc atg cggccc aac gac atc 1050 Met Ala Ala Leu Val Tyr Tyr Gly Phe Arg Met Arg ProAsn Asp Ile 270 275 280 gtc tat gac tgc ctc ccc ctc tac cac tca gca ggaaac atc gtg gga 1098 Val Tyr Asp Cys Leu Pro Leu Tyr His Ser Ala Gly AsnIle Val Gly 285 290 295 atc ggc cag tgc ctg ctg cat ggc atg acg gtg gtgatt cgg aag aag 1146 Ile Gly Gln Cys Leu Leu His Gly Met Thr Val Val IleArg Lys Lys 300 305 310 ttc tca gcc tcc cgg ttc tgg gac gat tgt atc aagtac aac tgc acg 1194 Phe Ser Ala Ser Arg Phe Trp Asp Asp Cys Ile Lys TyrAsn Cys Thr 315 320 325 att gtg cag tac att ggt gaa ctg tgc cgc tac ctcctg aac cag cca 1242 Ile Val Gln Tyr Ile Gly Glu Leu Cys Arg Tyr Leu LeuAsn Gln Pro 330 335 340 345 ccg cgg gag gca gaa aac cag cac cag gtt cgcatg gca cta ggc aat 1290 Pro Arg Glu Ala Glu Asn Gln His Gln Val Arg MetAla Leu Gly Asn 350 355 360 ggc ctc cgg cag tcc atc tgg acc aac ttt tccagc cgc ttc cac ata 1338 Gly Leu Arg Gln Ser Ile Trp Thr Asn Phe Ser SerArg Phe His Ile 365 370 375 ccc cag gtg gct gag ttc tac ggg gcc aca gagtgc aac tgt agc ctg 1386 Pro Gln Val Ala Glu Phe Tyr Gly Ala Thr Glu CysAsn Cys Ser Leu 380 385 390 ggc aac ttc gac agc cag gtg ggg gcc tgt ggtttc aat agc cgc atc 1434 Gly Asn Phe Asp Ser Gln Val Gly Ala Cys Gly PheAsn Ser Arg Ile 395 400 405 ctg tcc ttc gtg tac ccc atc cgg ttg gta cgtgtc aac gag gac acc 1482 Leu Ser Phe Val Tyr Pro Ile Arg Leu Val Arg ValAsn Glu Asp Thr 410 415 420 425 atg gag ctg atc cgg ggg ccc gac ggc gtctgc att ccc tgc cag cca 1530 Met Glu Leu Ile Arg Gly Pro Asp Gly Val CysIle Pro Cys Gln Pro 430 435 440 ggt gag ccg ggc cag ctg gtg ggc cgc atcatc cag aaa gac ccc ctg 1578 Gly Glu Pro Gly Gln Leu Val Gly Arg Ile IleGln Lys Asp Pro Leu 445 450 455 cgc cgc ttc gat ggc tac ctc aac cag ggcgcc aac aac aag aag att 1626 Arg Arg Phe Asp Gly Tyr Leu Asn Gln Gly AlaAsn Asn Lys Lys Ile 460 465 470 gcc aag gat gtc ttc aag aag ggg gac caggcc tac ctt act ggt gat 1674 Ala Lys Asp Val Phe Lys Lys Gly Asp Gln AlaTyr Leu Thr Gly Asp 475 480 485 gtg ctg gtg atg gac gag ctg ggc tac ctgtac ttc cga gac cgc act 1722 Val Leu Val Met Asp Glu Leu Gly Tyr Leu TyrPhe Arg Asp Arg Thr 490 495 500 505 ggg gac acg ttc cgc tgg aaa ggt gagaac gtg tcc acc acc gag gtg 1770 Gly Asp Thr Phe Arg Trp Lys Gly Glu AsnVal Ser Thr Thr Glu Val 510 515 520 gaa ggc aca ctc agc cgc ctg ctg gacatg gct gac gtg gcc gtg tat 1818 Glu Gly Thr Leu Ser Arg Leu Leu Asp MetAla Asp Val Ala Val Tyr 525 530 535 ggt gtc gag gtg cca gga acc gag ggccgg gcc gga atg gct gct gtg 1866 Gly Val Glu Val Pro Gly Thr Glu Gly ArgAla Gly Met Ala Ala Val 540 545 550 gcc agc ccc act ggc aac tgt gac ctggag cgc ttt gct cag gtc ttg 1914 Ala Ser Pro Thr Gly Asn Cys Asp Leu GluArg Phe Ala Gln Val Leu 555 560 565 gag aag gaa ctg ccc ctg tat gcg cgcccc atc ttc ctg cgc ctc ctg 1962 Glu Lys Glu Leu Pro Leu Tyr Ala Arg ProIle Phe Leu Arg Leu Leu 570 575 580 585 cct gag ctg cac aaa aca gga acctac aag ttc cag aag aca gag cta 2010 Pro Glu Leu His Lys Thr Gly Thr TyrLys Phe Gln Lys Thr Glu Leu 590 595 600 cgg aag gag ggc ttt gac ccg gctatt gtg aaa gac ccg ctg ttc tat 2058 Arg Lys Glu Gly Phe Asp Pro Ala IleVal Lys Asp Pro Leu Phe Tyr 605 610 615 cta gat gcc cag aag ggc cgc tacgtc ccg ctg gac caa gag gcc tac 2106 Leu Asp Ala Gln Lys Gly Arg Tyr ValPro Leu Asp Gln Glu Ala Tyr 620 625 630 agc cgc atc cag gca ggc gag gagaag ctg tgattccccc catccctctg 2156 Ser Arg Ile Gln Ala Gly Glu Glu LysLeu 635 640 agggccggcg gatgctggat ccggagcccc aggttccgcc ccagagcggtcctggacaag 2216 gccagaccaa agcaagcagg gcctggcacc tccatcctga ggtgctgcccctccatccaa 2276 aactgccaag tgactcattg ccttcccaac ccttccagag gctttctgtgaaagtctcat 2336 gtccaagttc cgtcttctgg gctgggcagg ccctctggtt cccaggctgagactgacggg 2396 ttttctcagg atgatgtctt gggtgagggt agggagagga caaggggtcaccgagccctt 2456 cccagagagc agggagctta taaatggaac cagagcagaa gtccccagactcaggaagtc 2516 aacagagtgg gcagggacag tggtagcatc catctggtgg ccaaagagaatcgtagcccc 2576 agagctgccc aagttcactg ggctccaccc ccacctccag gaggggaggagaggacctga 2636 catctgtagg tggcccctga tgccccatct acagcaggag gtcaggaccacgcccctggc 2696 ctctccccac tcccccatcc tcctccctgg gtggctgcct gattatccctcaggcagggc 2756 ctctcagtcc ttgtgggtct gtgtcacctc catctcagtc ttggcctggctatgagggga 2816 ggaggaatgg gagagggggc tcaggggcca ataaactctg ccttgagtcctcctaaaaaa 2876 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa agggcggccg c 2917 <210>SEQ ID NO 27 <211> LENGTH: 643 <212> TYPE: PRT <213> ORGANISM: Homosapiens <400> SEQUENCE: 27 Met Leu Leu Gly Ala Ser Leu Val Gly Val LeuLeu Phe Ser Lys Leu 1 5 10 15 Val Leu Lys Leu Pro Trp Thr Gln Val GlyPhe Ser Leu Leu Phe Leu 20 25 30 Tyr Leu Gly Ser Gly Gly Trp Arg Phe IleArg Val Phe Ile Lys Thr 35 40 45 Ile Arg Arg Asp Ile Phe Gly Gly Leu ValLeu Leu Lys Val Lys Ala 50 55 60 Lys Val Arg Gln Cys Leu Gln Glu Arg ArgThr Val Pro Ile Leu Phe 65 70 75 80 Ala Ser Thr Val Arg Arg His Pro AspLys Thr Ala Leu Ile Phe Glu 85 90 95 Gly Thr Asp Thr His Trp Thr Phe ArgGln Leu Asp Glu Tyr Ser Ser 100 105 110 Ser Val Ala Asn Phe Leu Gln AlaArg Gly Leu Ala Ser Gly Asp Val 115 120 125 Ala Ala Ile Phe Met Glu AsnArg Asn Glu Phe Val Gly Leu Trp Leu 130 135 140 Gly Met Ala Lys Leu GlyVal Glu Ala Ala Leu Ile Asn Thr Asn Leu 145 150 155 160 Arg Arg Asp AlaLeu Leu His Cys Leu Thr Thr Ser Arg Ala Arg Ala 165 170 175 Leu Val PheGly Ser Glu Met Ala Ser Ala Ile Cys Glu Val His Ala 180 185 190 Ser LeuAsp Pro Ser Leu Ser Leu Phe Cys Ser Gly Ser Trp Glu Pro 195 200 205 GlyAla Val Pro Pro Ser Thr Glu His Leu Asp Pro Leu Leu Lys Asp 210 215 220Ala Pro Lys His Leu Pro Ser Cys Pro Asp Lys Gly Phe Thr Asp Lys 225 230235 240 Leu Phe Tyr Ile Tyr Thr Ser Gly Thr Thr Gly Leu Pro Lys Ala Ala245 250 255 Ile Val Val His Ser Arg Tyr Tyr Arg Met Ala Ala Leu Val TyrTyr 260 265 270 Gly Phe Arg Met Arg Pro Asn Asp Ile Val Tyr Asp Cys LeuPro Leu 275 280 285 Tyr His Ser Ala Gly Asn Ile Val Gly Ile Gly Gln CysLeu Leu His 290 295 300 Gly Met Thr Val Val Ile Arg Lys Lys Phe Ser AlaSer Arg Phe Trp 305 310 315 320 Asp Asp Cys Ile Lys Tyr Asn Cys Thr IleVal Gln Tyr Ile Gly Glu 325 330 335 Leu Cys Arg Tyr Leu Leu Asn Gln ProPro Arg Glu Ala Glu Asn Gln 340 345 350 His Gln Val Arg Met Ala Leu GlyAsn Gly Leu Arg Gln Ser Ile Trp 355 360 365 Thr Asn Phe Ser Ser Arg PheHis Ile Pro Gln Val Ala Glu Phe Tyr 370 375 380 Gly Ala Thr Glu Cys AsnCys Ser Leu Gly Asn Phe Asp Ser Gln Val 385 390 395 400 Gly Ala Cys GlyPhe Asn Ser Arg Ile Leu Ser Phe Val Tyr Pro Ile 405 410 415 Arg Leu ValArg Val Asn Glu Asp Thr Met Glu Leu Ile Arg Gly Pro 420 425 430 Asp GlyVal Cys Ile Pro Cys Gln Pro Gly Glu Pro Gly Gln Leu Val 435 440 445 GlyArg Ile Ile Gln Lys Asp Pro Leu Arg Arg Phe Asp Gly Tyr Leu 450 455 460Asn Gln Gly Ala Asn Asn Lys Lys Ile Ala Lys Asp Val Phe Lys Lys 465 470475 480 Gly Asp Gln Ala Tyr Leu Thr Gly Asp Val Leu Val Met Asp Glu Leu485 490 495 Gly Tyr Leu Tyr Phe Arg Asp Arg Thr Gly Asp Thr Phe Arg TrpLys 500 505 510 Gly Glu Asn Val Ser Thr Thr Glu Val Glu Gly Thr Leu SerArg Leu 515 520 525 Leu Asp Met Ala Asp Val Ala Val Tyr Gly Val Glu ValPro Gly Thr 530 535 540 Glu Gly Arg Ala Gly Met Ala Ala Val Ala Ser ProThr Gly Asn Cys 545 550 555 560 Asp Leu Glu Arg Phe Ala Gln Val Leu GluLys Glu Leu Pro Leu Tyr 565 570 575 Ala Arg Pro Ile Phe Leu Arg Leu LeuPro Glu Leu His Lys Thr Gly 580 585 590 Thr Tyr Lys Phe Gln Lys Thr GluLeu Arg Lys Glu Gly Phe Asp Pro 595 600 605 Ala Ile Val Lys Asp Pro LeuPhe Tyr Leu Asp Ala Gln Lys Gly Arg 610 615 620 Tyr Val Pro Leu Asp GlnGlu Ala Tyr Ser Arg Ile Gln Ala Gly Glu 625 630 635 640 Glu Lys Leu<210> SEQ ID NO 28 <211> LENGTH: 1941 <212> TYPE: DNA <213> ORGANISM:Homo sapiens <400> SEQUENCE: 28 atgcgggctc cgggtgcggg cgcggcctcggtggtctcgc tggcgctgtt gtggctgctg 60 gggctgccgt ggacctggag cgcggcagcggcgctcggcg tgtacgtggg cagcggcggc 120 tggcgcttcc tgcgcatcgt ctgcaagaccgcgaggcgag acctcttcgg tctctctgtg 180 ctgatccgcg tgcgcctgga gctgcggcggcaccagcgtg ccggccacac catcccgcgc 240 atctttcagg cggtagtgca gcgacagcccgagcgcctgg cgctggtgga tgccgggacc 300 ggcgagtgct ggacctttgc gcagctggacgcctactcca atgcggtagc caacctcttc 360 cgccagctgg gcttcgcgcc gggcgacgtggtggccatct tcctggaggg ccggccggag 420 ttcgtggggc tgtggctggg cctggccaaggcgggcatgg aggccgcgct gctcaacgtg 480 aacctgcggc gcgagcccct ggccttctgcctgggcacct cgggcgctaa ggccctgatc 540 tttggaggag aaatggtggc ggcggtggccgaagtgagcg ggcatctggg gaaaagtttg 600 atcaagttct gctctggaga cttggggcccgagggcatct tgccggacac ccacctcctg 660 gacccgctgc tgaaggaggc ctctactgcccccttggcac agatccccag caagggcatg 720 gacgatcgtc ttttctacat ctacacgtcggggaccaccg ggctgcccaa ggctgccatt 780 gtcgtgcaca gcaggtacta ccgcatggcagccttcggcc accacgccta ccgcatgcag 840 gcggctgacg tgctctatga ctgcctgcccctgtaccact cggcaggaaa catcatcggc 900 gtggggcagt gtctcatcta tgggctgacagtcgtcctcc gcaagaaatt ctcggccagc 960 cgcttctggg acgactgcat caagtacaactgcacggtgg ttcagtacat cggggagatc 1020 tgccgctacc tgctgaagca gccggtgcgcgaggcggaga ggcgacaccg cgtgcgcctg 1080 gcggtgggga acgggctgcg tcctgccatctgggaggagt tcacggagcg cttcggcgta 1140 cgccaaatcg gggagttcta cggcgccaccgagtgcaact gcagcattgc caacatggac 1200 ggcaaggtcg gctcctgtgg tttcaacagccgcatcctgc cccacgtgta ccccatccgg 1260 ctggtgaagg tcaatgagga cacaatggagctgctgcggg atgcccaggg cctctgcatc 1320 ccctgccagg ccggggagcc tggcctccttgtgggtcaga tcaaccaaca ggacccgctg 1380 cgccgcttcg atggctatgt cagcgagagcgccaccagca agaagatcgc ccacagcgtc 1440 ttcagcaagg gcgacagcgc ctacctctcaggtgacgtgc tagtgatgga tgagctgggc 1500 tacatgtact tccgggaccg tagcggggacaccttccgct ggcgagggga gaacgtctcc 1560 accaccgagg tggagggcgt gctgagccgcctgctgggcc agacagacgt ggccgtctat 1620 ggggtggctg ttccaggagt ggagggtaaggcagggatgg cggccgtcgc agacccccac 1680 agcctgctgg accccaacgc gatataccaggagctgcaga aggtgctggc accctatgcc 1740 cggcccatct tcctgcgcct cctgccccaggtggacacca caggcacctt caagatccag 1800 aagacgaggc tgcagcgaga gggctttgacccacgccaga cctcagaccg gctcttcttc 1860 ctggacctga agcagggcca ctacctgcccttaaatgagg cagtctacac tcgcatctgc 1920 tcgggcgcct tcgccctctg a 1941 <210>SEQ ID NO 29 <211> LENGTH: 1938 <212> TYPE: DNA <213> ORGANISM: Musmusculus <400> SEQUENCE: 29 atgcgggctc ctggagcagg aacagcctct gtggcctcactggcgctgct ttggtttctg 60 ggacttccgt ggacctggag cgcggcggcg gcgttctgtgtgtacgtggg tggcggcggc 120 tggcgctttc tgcgtatcgt ctgcaagacg gcgaggcgagacctctttgg cctctctgtt 180 ctgattcgtg ttcggctaga gctgcgacga caccggcgagcaggagacac gatcccgtgc 240 atcttccagg ctgtggcccg gcgacaacca gagcgcctggcactggtgga cgccagtagt 300 ggtatatgct ggaccttcgc acagctggac acctactccaatgctgtagc caacctgttc 360 cgccagctgg gctttgcacc aggcgatgtg gtggctgtgttcctggaggg ccggccggag 420 ttcgtgggac tgtggctggg cctggccaag gccggtgtggtggctgctct tctcaatgtc 480 aacctgaggc gggagcccct ggccttctgc ctgggcacatcagctgccaa ggccctcatt 540 tatggcgggg agatggcagc ggcggtggcg gaggtgagcgagcagctggg gaagagcctc 600 ctcaagttct gctctggaga tctggggcct gagagcatcctgcctgacac gcagctcctg 660 gaccccatgc ttgctgaggc gcccaccaca cccctggcacaagccccagg caagggcatg 720 gatgatcggc tgttttacat ctatacttct gggaccaccgggcttcctaa ggctgccatt 780 gtggtgcaca gcaggtacta ccgcattgct gcctttggccaccattccta cagcatgcgt 840 gccgccgatg tgctctatga ctgcctgcca ctctaccactctgcagggaa catcatgggt 900 gtggggcagt gcgtcatcta cgggttgacg gtggtactgcgcaagaagtt ctccgccagc 960 cgcttctggg atgactgtgt caagtacaat tgcacggtagtgcagtacat aggtgaaatc 1020 tgccgctacc tgctgaggca gccggttcgc gacgtggagcagcgacaccg cgtgcgcctg 1080 gccgtgggta atgggctgcg gccagccatc tgggaggagttcacgcagcg cttcggtgtg 1140 ccacagatcg gcgagttcta cggcgctacc gagtgcaactgcagcattgc caacatggac 1200 ggcaaggtcg gctcctgcgg cttcaacagc cgtatcctcacgcatgtgta ccccatccgt 1260 ctggtcaagg tcaatgagga cacgatggag ccactgcgggactccgaggg cctctgcatc 1320 ccgtgccagc ccggggaacc cggccttctc gtgggccagatcaaccagca ggaccctctg 1380 cggcgtttcg atggttatgt tagtgacagt gccaccaacaagaagattgc ccacagcgtt 1440 ttccgaaagg gcgatagcgc ctacctctca ggtgacgtgctagtgatgga cgagctgggc 1500 tacatgtatt tccgtgaccg cagcggggac accttccgctggcgcgggga gaacgtgtcc 1560 accacggagg tggaagccgt gctgagccgc ctactgggccagacggacgt ggctgtgtat 1620 ggggtggctg tgccaggagt ggaggggaaa gctggcatggcagccatcgc agatccccac 1680 agccagttgg accctaactc aatgtaccag gaattacagaaggttcttgc atcctatgct 1740 cggcccatct tcctgcgtct tctgccccag gtggataccacaggcacctt caagatccag 1800 aagacccggc tgcagcgtga aggctttgac ccccgtcagacctcagacag gctcttcttt 1860 ctagacctga agcagggacg ctatgtaccc ctggatgagagagtccatgc ccgcatttgt 1920 gcaggcgact tctcactc 1938 <210> SEQ ID NO 30<211> LENGTH: 1896 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400>SEQUENCE: 30 ctgttctcca agctggtgct gaaactgccc tggacccagg tgggattctccctgttgttc 60 ctctacttgg gatctggcgg ctggcgcttc atccgggtct tcatcaagaccatcaggcgc 120 gatatctttg gcggcctggt cctcctgaag gtgaaggcaa aggtgcgacagtgcctgcag 180 gagcggcgga cagtgcccat tttgtttgcc tctaccgttc ggcgccaccccgacaagacg 240 gccctgatct tcgagggcac agatacccac tggaccttcc gccagctggatgagtactca 300 agcagtgtag ccaacttcct gcaggcccgg ggcctggcct cgggcgatgtggctgccatc 360 ttcatggaga accgcaatga gttcgtgggc ctatggctgg gcatggccaagctcggtgtg 420 gaggcagccc tcatcaacac caacctgcgg cgggatgctc tgctccactgcctcaccacc 480 tcgcgcgcac gggcccttgt ctttggcagc gaaatggcct cagccatctgtgaggtccat 540 gccagcctgg acccctcgct cagcctcttc tgctctggct cctgggagcccggtgcggtg 600 cctccaagca cagaacacct ggaccctctg ctgaaagatg ctcccaagcaccttcccagt 660 tgccctgaca agggcttcac agataaactg ttctacatct acacatccggcaccacaggg 720 ctgcccaagg ccgccatcgt ggtgcacagc aggtattacc gcatggctgccctggtgtac 780 tatggattcc gcatgcggcc caacgacatc gtctatgact gcctccccctctaccactca 840 gcaggaaaca tcgtgggaat cggccagtgc ctgctgcatg gcatgacggtggtgattcgg 900 aagaagttct cagcctcccg gttctgggac gattgtatca agtacaactgcacgattgtg 960 cagtacattg gtgaactgtg ccgctacctc ctgaaccagc caccgcgggaggcagaaaac 1020 cagcaccagg ttcgcatggc actaggcaat ggcctccggc agtccatctggaccaacttt 1080 tccagccgct tccacatacc ccaggtggct gagttctacg gggccacagagtgcaactgt 1140 agcctgggca acttcgacag ccaggtgggg gcctgtggtt tcaatagccgcatcctgtcc 1200 ttcgtgtacc ccatccggtt ggtacgtgtc aacgaggaca ccatggagctgatccggggg 1260 cccgacggcg tctgcattcc ctgccagcca ggtgagccgg gccagctggtgggccgcatc 1320 atccagaaag accccctgcg ccgcttcgat ggctacctca accagggcgccaacaacaag 1380 aagattgcca aggatgtctt caagaagggg gaccaggcct accttactggtgatgtgctg 1440 gtgatggacg agctgggcta cctgtacttc cgagaccgca ctggggacacgttccgctgg 1500 aaaggtgaga acgtgtccac caccgaggtg gaaggcacac tcagccgcctgctggacatg 1560 gctgacgtgg ccgtgtatgg tgtcgaggtg ccaggaaccg agggccgggccggaatggct 1620 gctgtggcca gccccactgg caactgtgac ctggagcgct ttgctcaggtcttggagaag 1680 gaactgcccc tgtatgcgcg ccccatcttc ctgcgcctcc tgcctgagctgcacaaaaca 1740 ggaacctaca agttccagaa gacagagcta cggaaggagg gctttgacccggctattgtg 1800 aaagacccgc tgttctatct agatgcccag aagggccgct acgtcccgctggaccaagag 1860 gcctacagcc gcatccaggc aggcgaggag aagctg 1896 <210> SEQID NO 31 <211> LENGTH: 1896 <212> TYPE: DNA <213> ORGANISM: Mus musculus<400> SEQUENCE: 31 cttgggtcca agctagtgct gaagctgccc tggacccaggtgggattctc cctgttgctc 60 ctgtacttgg ggtctggtgg ctggcgtttc atccgggtcttcatcaagac ggtcaggaga 120 gatatctttg gtggcatggt gctcctgaag gtgaagaccaaggtgcgacg gtaccttcag 180 gagcggaaga cggtgcccct gctgtttgct tcaatggtacagcgccaccc ggacaagaca 240 gccctgattt tcgagggcac agacactcac tggaccttccgccagctgga tgagtactcc 300 agtagtgtgg ccaacttcct gcaggcccgg ggcctggcctcaggcaatgt agttgccctc 360 tttatggaaa accgcaatga gtttgtgggt ctgtggctaggcatggccaa gctgggcgtg 420 gaggcggctc tcatcaacac caaccttagg cgggatgccctgcgccactg tcttgacacc 480 tcaaaggcac gagctctcat ctttggcagt gagatggcctcagctatctg tgagatccat 540 gctagcctgg agcccacact cagcctcttc tgctctggatcctgggagcc cagcacagtg 600 cccgtcagca cagagcatct ggaccctctt ctggaagatgccccgaagca cctgcccagt 660 cacccagaca agggttttac agataagctc ttctacatctacacatcggg caccacgggg 720 ctacccaaag ctgccattgt ggtgcacagc aggtattatcgtatggcttc cctggtgtac 780 tatggattcc gcatgcggcc tgatgacatt gtctatgactgcctccccct ctaccactca 840 agcaggaaac atcgtgggga ttggcagtgc ttactccacggcatgactgt ggtgatccgg 900 aagaagttct cagcctcccg gttctgggat gattgtatcaagtacaactg cacagtggta 960 cagtacattg gcgagctctg ccgctacctc ctgaaccagccaccccgtga ggctgagtct 1020 cggcacaagg tgcgcatggc actgggcaac ggtctccggcagtccatctg gaccgacttc 1080 tccagccgtt tccacatccc ccaggtggct gagttctatggggccactga atgcaactgt 1140 agcctgggca actttgacag ccgggtgggg gcctgtggcttcaatagccg catcctgtcc 1200 tttgtgtacc ctatccgttt ggtacgtgtc aatgaggataccatggaact gatccgggga 1260 cccgatggag tctgcattcc ctgtcaacca ggtcagccaggccagctggt gggtcgcatc 1320 atccagcagg accctctgcg ccgtttcgac gggtacctcaaccagggtgc caacaacaag 1380 aagattgcta atgatgtctt caagaagggg gaccaagcctacctcactgg tgacgtcctg 1440 gtgatggatg agctgggtta cctgtacttc cgagatcgcactggggacac gttccgctgg 1500 aaaggggaga atgtatctac cactgaggtg gagggcacactcagccgcct gcttcatatg 1560 gcagatgtgg cagtttatgg tgttgaggtg ccaggaactgaaggccgagc aggaatggct 1620 gccgttgcaa gtcccatcag caactgtgac ctggagagctttgcacagac cttgaaaaag 1680 gagctgcctc tgtatgcccg ccccatcttc ctgcgcttcttgcctgagct gcacaagaca 1740 gggaccttca agttccagaa gacagagttg cggaaggagggctttgaccc atctgttgtg 1800 aaagacccgc tgttctatct ggatgctcgg aagggctgctacgttgcact ggaccaggag 1860 gcctataccc gcatccaggc aggcgaggag aagctg 1896<210> SEQ ID NO 32 <211> LENGTH: 646 <212> TYPE: PRT <213> ORGANISM:Homo sapiens <400> SEQUENCE: 32 Met Arg Ala Pro Gly Ala Gly Ala Ala SerVal Val Ser Leu Ala Leu 1 5 10 15 Leu Trp Leu Leu Gly Leu Pro Trp ThrTrp Ser Ala Ala Ala Ala Leu 20 25 30 Gly Val Tyr Val Gly Ser Gly Gly TrpArg Phe Leu Arg Ile Val Cys 35 40 45 Lys Thr Ala Arg Arg Asp Leu Phe GlyLeu Ser Val Leu Ile Arg Val 50 55 60 Arg Leu Glu Leu Arg Arg His Gln ArgAla Gly His Thr Ile Pro Arg 65 70 75 80 Ile Phe Gln Ala Val Val Gln ArgGln Pro Glu Arg Leu Ala Leu Val 85 90 95 Asp Ala Gly Thr Gly Glu Cys TrpThr Phe Ala Gln Leu Asp Ala Tyr 100 105 110 Ser Asn Ala Val Ala Asn LeuPhe Arg Gln Leu Gly Phe Ala Pro Gly 115 120 125 Asp Val Val Ala Ile PheLeu Glu Gly Arg Pro Glu Phe Val Gly Leu 130 135 140 Trp Leu Gly Leu AlaLys Ala Gly Met Glu Ala Ala Leu Leu Asn Val 145 150 155 160 Asn Leu ArgArg Glu Pro Leu Ala Phe Cys Leu Gly Thr Ser Gly Ala 165 170 175 Lys AlaLeu Ile Phe Gly Gly Glu Met Val Ala Ala Val Ala Glu Val 180 185 190 SerGly His Leu Gly Lys Ser Leu Ile Lys Phe Cys Ser Gly Asp Leu 195 200 205Gly Pro Glu Gly Ile Leu Pro Asp Thr His Leu Leu Asp Pro Leu Leu 210 215220 Lys Glu Ala Ser Thr Ala Pro Leu Ala Gln Ile Pro Ser Lys Gly Met 225230 235 240 Asp Asp Arg Leu Phe Tyr Ile Tyr Thr Ser Gly Thr Thr Gly LeuPro 245 250 255 Lys Ala Ala Ile Val Val His Ser Arg Tyr Tyr Arg Met AlaAla Phe 260 265 270 Gly His His Ala Tyr Arg Met Gln Ala Ala Asp Val LeuTyr Asp Cys 275 280 285 Leu Pro Leu Tyr His Ser Ala Gly Asn Ile Ile GlyVal Gly Gln Cys 290 295 300 Leu Ile Tyr Gly Leu Thr Val Val Leu Arg LysLys Phe Ser Ala Ser 305 310 315 320 Arg Phe Trp Asp Asp Cys Ile Lys TyrAsn Cys Thr Val Val Gln Tyr 325 330 335 Ile Gly Glu Ile Cys Arg Tyr LeuLeu Lys Gln Pro Val Arg Glu Ala 340 345 350 Glu Arg Arg His Arg Val ArgLeu Ala Val Gly Asn Gly Leu Arg Pro 355 360 365 Ala Ile Trp Glu Glu PheThr Glu Arg Phe Gly Val Arg Gln Ile Gly 370 375 380 Glu Phe Tyr Gly AlaThr Glu Cys Asn Cys Ser Ile Ala Asn Met Asp 385 390 395 400 Gly Lys ValGly Ser Cys Gly Phe Asn Ser Arg Ile Leu Pro His Val 405 410 415 Tyr ProIle Arg Leu Val Lys Val Asn Glu Asp Thr Met Glu Leu Leu 420 425 430 ArgAsp Ala Gln Gly Leu Cys Ile Pro Cys Gln Ala Gly Glu Pro Gly 435 440 445Leu Leu Val Gly Gln Ile Asn Gln Gln Asp Pro Leu Arg Arg Phe Asp 450 455460 Gly Tyr Val Ser Glu Ser Ala Thr Ser Lys Lys Ile Ala His Ser Val 465470 475 480 Phe Ser Lys Gly Asp Ser Ala Tyr Leu Ser Gly Asp Val Leu ValMet 485 490 495 Asp Glu Leu Gly Tyr Met Tyr Phe Arg Asp Arg Ser Gly AspThr Phe 500 505 510 Arg Trp Arg Gly Glu Asn Val Ser Thr Thr Glu Val GluGly Val Leu 515 520 525 Ser Arg Leu Leu Gly Gln Thr Asp Val Ala Val TyrGly Val Ala Val 530 535 540 Pro Gly Val Glu Gly Lys Ala Gly Met Ala AlaVal Ala Asp Pro His 545 550 555 560 Ser Leu Leu Asp Pro Asn Ala Ile TyrGln Glu Leu Gln Lys Val Leu 565 570 575 Ala Pro Tyr Ala Arg Pro Ile PheLeu Arg Leu Leu Pro Gln Val Asp 580 585 590 Thr Thr Gly Thr Phe Lys IleGln Lys Thr Arg Leu Gln Arg Glu Gly 595 600 605 Phe Asp Pro Arg Gln ThrSer Asp Arg Leu Phe Phe Leu Asp Leu Lys 610 615 620 Gln Gly His Tyr LeuPro Leu Asn Glu Ala Val Tyr Thr Arg Ile Cys 625 630 635 640 Ser Gly AlaPhe Ala Leu 645 <210> SEQ ID NO 33 <211> LENGTH: 646 <212> TYPE: PRT<213> ORGANISM: Mus musculus <400> SEQUENCE: 33 Met Arg Ala Pro Gly AlaGly Thr Ala Ser Val Ala Ser Leu Ala Leu 1 5 10 15 Leu Trp Phe Leu GlyLeu Pro Trp Thr Trp Ser Ala Ala Ala Ala Phe 20 25 30 Cys Val Tyr Val GlyGly Gly Gly Trp Arg Phe Leu Arg Ile Val Cys 35 40 45 Lys Thr Ala Arg ArgAsp Leu Phe Gly Leu Ser Val Leu Ile Arg Val 50 55 60 Arg Leu Glu Leu ArgArg His Arg Arg Ala Gly Asp Thr Ile Pro Cys 65 70 75 80 Ile Phe Gln AlaVal Ala Arg Arg Gln Pro Glu Arg Leu Ala Leu Val 85 90 95 Asp Ala Ser SerGly Ile Cys Trp Thr Phe Ala Gln Leu Asp Thr Tyr 100 105 110 Ser Asn AlaVal Ala Asn Leu Phe Arg Gln Leu Gly Phe Ala Pro Gly 115 120 125 Asp ValVal Ala Val Phe Leu Glu Gly Arg Pro Glu Phe Val Gly Leu 130 135 140 TrpLeu Gly Leu Ala Lys Ala Gly Val Val Ala Ala Leu Leu Asn Val 145 150 155160 Asn Leu Arg Arg Glu Pro Leu Ala Phe Cys Leu Gly Thr Ser Ala Ala 165170 175 Lys Ala Leu Ile Tyr Gly Gly Glu Met Ala Ala Ala Val Ala Glu Val180 185 190 Ser Glu Gln Leu Gly Lys Ser Leu Leu Lys Phe Cys Ser Gly AspLeu 195 200 205 Gly Pro Glu Ser Ile Leu Pro Asp Thr Gln Leu Leu Asp ProMet Leu 210 215 220 Ala Glu Ala Pro Thr Thr Pro Leu Ala Gln Ala Pro GlyLys Gly Met 225 230 235 240 Asp Asp Arg Leu Phe Tyr Ile Tyr Thr Ser GlyThr Thr Gly Leu Pro 245 250 255 Lys Ala Ala Ile Val Val His Ser Arg TyrTyr Arg Ile Ala Ala Phe 260 265 270 Gly His His Ser Tyr Ser Met Arg AlaAla Asp Val Leu Tyr Asp Cys 275 280 285 Leu Pro Leu Tyr His Ser Ala GlyAsn Ile Met Gly Val Gly Gln Cys 290 295 300 Val Ile Tyr Gly Leu Thr ValVal Leu Arg Lys Lys Phe Ser Ala Ser 305 310 315 320 Arg Phe Trp Asp AspCys Val Lys Tyr Asn Cys Thr Val Val Gln Tyr 325 330 335 Ile Gly Glu IleCys Arg Tyr Leu Leu Arg Gln Pro Val Arg Asp Val 340 345 350 Glu Gln ArgHis Arg Val Arg Leu Ala Val Gly Asn Gly Leu Arg Pro 355 360 365 Ala IleTrp Glu Glu Phe Thr Gln Arg Phe Gly Val Pro Gln Ile Gly 370 375 380 GluPhe Tyr Gly Ala Thr Glu Cys Asn Cys Ser Ile Ala Asn Met Asp 385 390 395400 Gly Lys Val Gly Ser Cys Gly Phe Asn Ser Arg Ile Leu Thr His Val 405410 415 Tyr Pro Ile Arg Leu Val Lys Val Asn Glu Asp Thr Met Glu Pro Leu420 425 430 Arg Asp Ser Glu Gly Leu Cys Ile Pro Cys Gln Pro Gly Glu ProGly 435 440 445 Leu Leu Val Gly Gln Ile Asn Gln Gln Asp Pro Leu Arg ArgPhe Asp 450 455 460 Gly Tyr Val Ser Asp Ser Ala Thr Asn Lys Lys Ile AlaHis Ser Val 465 470 475 480 Phe Arg Lys Gly Asp Ser Ala Tyr Leu Ser GlyAsp Val Leu Val Met 485 490 495 Asp Glu Leu Gly Tyr Met Tyr Phe Arg AspArg Ser Gly Asp Thr Phe 500 505 510 Arg Trp Arg Gly Glu Asn Val Ser ThrThr Glu Val Glu Ala Val Leu 515 520 525 Ser Arg Leu Leu Gly Gln Thr AspVal Ala Val Tyr Gly Val Ala Val 530 535 540 Pro Gly Val Glu Gly Lys AlaGly Met Ala Ala Ile Ala Asp Pro His 545 550 555 560 Ser Gln Leu Asp ProAsn Ser Met Tyr Gln Glu Leu Gln Lys Val Leu 565 570 575 Ala Ser Tyr AlaArg Pro Ile Phe Leu Arg Leu Leu Pro Gln Val Asp 580 585 590 Thr Thr GlyThr Phe Lys Ile Gln Lys Thr Arg Leu Gln Arg Glu Gly 595 600 605 Phe AspPro Arg Gln Thr Ser Asp Arg Leu Phe Phe Leu Asp Leu Lys 610 615 620 GlnGly Arg Tyr Val Pro Leu Asp Glu Arg Val His Ala Arg Ile Cys 625 630 635640 Ala Gly Asp Phe Ser Leu 645 <210> SEQ ID NO 34 <211> LENGTH: 632<212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 34 Leu PheSer Lys Leu Val Leu Lys Leu Pro Trp Thr Gln Val Gly Phe 1 5 10 15 SerLeu Leu Phe Leu Tyr Leu Gly Ser Gly Gly Trp Arg Phe Ile Arg 20 25 30 ValPhe Ile Lys Thr Ile Arg Arg Asp Ile Phe Gly Gly Leu Val Leu 35 40 45 LeuLys Val Lys Ala Lys Val Arg Gln Cys Leu Gln Glu Arg Arg Thr 50 55 60 ValPro Ile Leu Phe Ala Ser Thr Val Arg Arg His Pro Asp Lys Thr 65 70 75 80Ala Leu Ile Phe Glu Gly Thr Asp Thr His Trp Thr Phe Arg Gln Leu 85 90 95Asp Glu Tyr Ser Ser Ser Val Ala Asn Phe Leu Gln Ala Arg Gly Leu 100 105110 Ala Ser Gly Asp Val Ala Ala Ile Phe Met Glu Asn Arg Asn Glu Phe 115120 125 Val Gly Leu Trp Leu Gly Met Ala Lys Leu Gly Val Glu Ala Ala Leu130 135 140 Ile Asn Thr Asn Leu Arg Arg Asp Ala Leu Leu His Cys Leu ThrThr 145 150 155 160 Ser Arg Ala Arg Ala Leu Val Phe Gly Ser Glu Met AlaSer Ala Ile 165 170 175 Cys Glu Val His Ala Ser Leu Asp Pro Ser Leu SerLeu Phe Cys Ser 180 185 190 Gly Ser Trp Glu Pro Gly Ala Val Pro Pro SerThr Glu His Leu Asp 195 200 205 Pro Leu Leu Lys Asp Ala Pro Lys His LeuPro Ser Cys Pro Asp Lys 210 215 220 Gly Phe Thr Asp Lys Leu Phe Tyr IleTyr Thr Ser Gly Thr Thr Gly 225 230 235 240 Leu Pro Lys Ala Ala Ile ValVal His Ser Arg Tyr Tyr Arg Met Ala 245 250 255 Ala Leu Val Tyr Tyr GlyPhe Arg Met Arg Pro Asn Asp Ile Val Tyr 260 265 270 Asp Cys Leu Pro LeuTyr His Ser Ala Gly Asn Ile Val Gly Ile Gly 275 280 285 Gln Cys Leu LeuHis Gly Met Thr Val Val Ile Arg Lys Lys Phe Ser 290 295 300 Ala Ser ArgPhe Trp Asp Asp Cys Ile Lys Tyr Asn Cys Thr Ile Val 305 310 315 320 GlnTyr Ile Gly Glu Leu Cys Arg Tyr Leu Leu Asn Gln Pro Pro Arg 325 330 335Glu Ala Glu Asn Gln His Gln Val Arg Met Ala Leu Gly Asn Gly Leu 340 345350 Arg Gln Ser Ile Trp Thr Asn Phe Ser Ser Arg Phe His Ile Pro Gln 355360 365 Val Ala Glu Phe Tyr Gly Ala Thr Glu Cys Asn Cys Ser Leu Gly Asn370 375 380 Phe Asp Ser Gln Val Gly Ala Cys Gly Phe Asn Ser Arg Ile LeuSer 385 390 395 400 Phe Val Tyr Pro Ile Arg Leu Val Arg Val Asn Glu AspThr Met Glu 405 410 415 Leu Ile Arg Gly Pro Asp Gly Val Cys Ile Pro CysGln Pro Gly Glu 420 425 430 Pro Gly Gln Leu Val Gly Arg Ile Ile Gln LysAsp Pro Leu Arg Arg 435 440 445 Phe Asp Gly Tyr Leu Asn Gln Gly Ala AsnAsn Lys Lys Ile Ala Lys 450 455 460 Asp Val Phe Lys Lys Gly Asp Gln AlaTyr Leu Thr Gly Asp Val Leu 465 470 475 480 Val Met Asp Glu Leu Gly TyrLeu Tyr Phe Arg Asp Arg Thr Gly Asp 485 490 495 Thr Phe Arg Trp Lys GlyGlu Asn Val Ser Thr Thr Glu Val Glu Gly 500 505 510 Thr Leu Ser Arg LeuLeu Asp Met Ala Asp Val Ala Val Tyr Gly Val 515 520 525 Glu Val Pro GlyThr Glu Gly Arg Ala Gly Met Ala Ala Val Ala Ser 530 535 540 Pro Thr GlyAsn Cys Asp Leu Glu Arg Phe Ala Gln Val Leu Glu Lys 545 550 555 560 GluLeu Pro Leu Tyr Ala Arg Pro Ile Phe Leu Arg Leu Leu Pro Glu 565 570 575Leu His Lys Thr Gly Thr Tyr Lys Phe Gln Lys Thr Glu Leu Arg Lys 580 585590 Glu Gly Phe Asp Pro Ala Ile Val Lys Asp Pro Leu Phe Tyr Leu Asp 595600 605 Ala Gln Lys Gly Arg Tyr Val Pro Leu Asp Gln Glu Ala Tyr Ser Arg610 615 620 Ile Gln Ala Gly Glu Glu Lys Leu 625 630 <210> SEQ ID NO 35<211> LENGTH: 632 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400>SEQUENCE: 35 Leu Gly Ser Lys Leu Val Leu Lys Leu Pro Trp Thr Gln Val GlyPhe 1 5 10 15 Ser Leu Leu Leu Leu Tyr Leu Gly Ser Gly Gly Trp Arg PheIle Arg 20 25 30 Val Phe Ile Lys Thr Val Arg Arg Asp Ile Phe Gly Gly MetVal Leu 35 40 45 Leu Lys Val Lys Thr Lys Val Arg Arg Tyr Leu Gln Glu ArgLys Thr 50 55 60 Val Pro Leu Leu Phe Ala Ser Met Val Gln Arg His Pro AspLys Thr 65 70 75 80 Ala Leu Ile Phe Glu Gly Thr Asp Thr His Trp Thr PheArg Gln Leu 85 90 95 Asp Glu Tyr Ser Ser Ser Val Ala Asn Phe Leu Gln AlaArg Gly Leu 100 105 110 Ala Ser Gly Asn Val Val Ala Leu Phe Met Glu AsnArg Asn Glu Phe 115 120 125 Val Gly Leu Trp Leu Gly Met Ala Lys Leu GlyVal Glu Ala Ala Leu 130 135 140 Ile Asn Thr Asn Leu Arg Arg Asp Ala LeuArg His Cys Leu Asp Thr 145 150 155 160 Ser Lys Ala Arg Ala Leu Ile PheGly Ser Glu Met Ala Ser Ala Ile 165 170 175 Cys Glu Ile His Ala Ser LeuGlu Pro Thr Leu Ser Leu Phe Cys Ser 180 185 190 Gly Ser Trp Glu Pro SerThr Val Pro Val Ser Thr Glu His Leu Asp 195 200 205 Pro Leu Leu Glu AspAla Pro Lys His Leu Pro Ser His Pro Asp Lys 210 215 220 Gly Phe Thr AspLys Leu Phe Tyr Ile Tyr Thr Ser Gly Thr Thr Gly 225 230 235 240 Leu ProLys Ala Ala Ile Val Val His Ser Arg Tyr Tyr Arg Met Ala 245 250 255 SerLeu Val Tyr Tyr Gly Phe Arg Met Arg Pro Asp Asp Ile Val Tyr 260 265 270Asp Cys Leu Pro Leu Tyr His Ser Ser Arg Lys His Arg Gly Asp Trp 275 280285 Gln Cys Leu Leu His Gly Met Thr Val Val Ile Arg Lys Lys Phe Ser 290295 300 Ala Ser Arg Phe Trp Asp Asp Cys Ile Lys Tyr Asn Cys Thr Val Val305 310 315 320 Gln Tyr Ile Gly Glu Leu Cys Arg Tyr Leu Leu Asn Gln ProPro Arg 325 330 335 Glu Ala Glu Ser Arg His Lys Val Arg Met Ala Leu GlyAsn Gly Leu 340 345 350 Arg Gln Ser Ile Trp Thr Asp Phe Ser Ser Arg PheHis Ile Pro Gln 355 360 365 Val Ala Glu Phe Tyr Gly Ala Thr Glu Cys AsnCys Ser Leu Gly Asn 370 375 380 Phe Asp Ser Arg Val Gly Ala Cys Gly PheAsn Ser Arg Ile Leu Ser 385 390 395 400 Phe Val Tyr Pro Ile Arg Leu ValArg Val Asn Glu Asp Thr Met Glu 405 410 415 Leu Ile Arg Gly Pro Asp GlyVal Cys Ile Pro Cys Gln Pro Gly Gln 420 425 430 Pro Gly Gln Leu Val GlyArg Ile Ile Gln Gln Asp Pro Leu Arg Arg 435 440 445 Phe Asp Gly Tyr LeuAsn Gln Gly Ala Asn Asn Lys Lys Ile Ala Asn 450 455 460 Asp Val Phe LysLys Gly Asp Gln Ala Tyr Leu Thr Gly Asp Val Leu 465 470 475 480 Val MetAsp Glu Leu Gly Tyr Leu Tyr Phe Arg Asp Arg Thr Gly Asp 485 490 495 ThrPhe Arg Trp Lys Gly Glu Asn Val Ser Thr Thr Glu Val Glu Gly 500 505 510Thr Leu Ser Arg Leu Leu His Met Ala Asp Val Ala Val Tyr Gly Val 515 520525 Glu Val Pro Gly Thr Glu Gly Arg Ala Gly Met Ala Ala Val Ala Ser 530535 540 Pro Ile Ser Asn Cys Asp Leu Glu Ser Phe Ala Gln Thr Leu Lys Lys545 550 555 560 Glu Leu Pro Leu Tyr Ala Arg Pro Ile Phe Leu Arg Phe LeuPro Glu 565 570 575 Leu His Lys Thr Gly Thr Phe Lys Phe Gln Lys Thr GluLeu Arg Lys 580 585 590 Glu Gly Phe Asp Pro Ser Val Val Lys Asp Pro LeuPhe Tyr Leu Asp 595 600 605 Ala Arg Lys Gly Cys Tyr Val Ala Leu Asp GlnGlu Ala Tyr Thr Arg 610 615 620 Ile Gln Ala Gly Glu Glu Lys Leu 625 630<210> SEQ ID NO 36 <211> LENGTH: 2885 <212> TYPE: DNA <213> ORGANISM:Homo sapiens <400> SEQUENCE: 36 aacggcaagt aagcgcaacg caattaatgtgagtagctca ctcattaggc accccaggct 60 ttacacttta tgcttccggg ctcgtatgttgtgtggaatt gtgagcggat accaatttca 120 cacaggaacc agctatgaca tgattacgaatttaatacga ctcactatag ggaatttggc 180 cctcgaggcc aagaattcgg cacgaggggtgctgagcccc tgcgcggttt ctggtgcgta 240 gagactgtaa atcgctgcgc ttctcagtcatcatcatccc agcttttccc ggctcgaatt 300 cagcctccaa ctcaagctcg cgggaaagactacctgagag gagaaaagct tctgtccctg 360 gaccttcttc tgagggtgga gtcggaggctccctgctttc cagccgccca gtgacccaag 420 cttaatcttc agcaccactt ggggcgaccttttcggtgca aacctacgat tctgtttctc 480 aggattcctc cccatcccgc ttcgccccggaaaagctgac aagaacttca ggtgtaagcc 540 ctgagtagtg aggatctgcg gtctccgtggagagctgtgc ctggaagaga aggacgctgg 600 tgggggctga gatcagagct gtcttctggcccagttgccc ccatgcttct gtcatggcta 660 acagttctag gggctggaat ggtcgtcctgcacttcttgc agaaactcct gttcccttac 720 ttttgggatg acttctggtt cgtgttgaaggtggtgctca ttataattcg gctgaagaag 780 tatgaaaaga gaggggagct ggtgactgtgctggataaat tcttgagtca tgccaaaaga 840 caacctcgga aacctttcat catctatgagggagacatct acacctatca ggatgtagac 900 aaaaggagca gcagagtggc ccatgtcttcctgaaccatt cctctctgaa aaagggggac 960 acggtggctc tgctgatgag caatgagccggacttcgttc acgtgtggtt cggcctcgcc 1020 aagctgggct gcgtggtggc ctttctcaacaccaacattc gctccaactc cctcctgaat 1080 tgcatccgcg cctgtgggcc cagagccctagtggtgggcg cagatttgct tggaacggta 1140 gaagaaatcc ttccaagcct ctcagaaaatatcagtgttt gggggatgaa agattctgtt 1200 ccacaaggtg taatttcact caaagaaaaactgagcacct cacctgatga gcccgtgcca 1260 cgcagccacc atgttgtctc actcctcaagtctacttgtc tttacatttt tacctctgga 1320 acaacaggtc taccaaaagc agctgtgattagtcagctgc aggttttaag gggttctgct 1380 gtcctgtggg cttttggttg tactgctcatgacattgttt atataaccct tcctctgtat 1440 catagttcag cagctatcct gggaatttctggatgtgttg agttgggtgc cacttgtgtg 1500 ttaaagaaga aattttcagc aagccagttttggagtgact gcaagaagta tgatgtgact 1560 gtgtttcagt atattggaga actttgtcgctacctttgca aacaatctaa gagagaagga 1620 gaaaaggatc ataaggtgcg tttggcaattggaaatggca tacggagtga tgtatggaga 1680 gaatttttag acagatttgg aaatataaaggtgtgtgaac tttatgcagc taccgaatca 1740 agcatatctt tcatgaacta cactgggagaattggagcaa ttgggagaac aaatttgttt 1800 tacaaacttc tttccacttt tgacttaataaagtatgact ttcagaaaga tgaacccatg 1860 agaaatgagc agggttggtg tattcatgtgaaaaaaggag aacctggact tctcatttct 1920 cgagtgaatg caaaaaatcc cttctttggctatgctgggc cttataagca cacaaaagac 1980 aaattgcttt gtgatgtttt taagaagggagatgtttacc ttaatactgg agacttaata 2040 gtccaggatc aggacaattt cctttatttttgggaccgta ctggagacac tttcagatgg 2100 aaaggagaaa atgtcgcaac cactgaggttgctgatgtta ttggaatgtt ggatttcata 2160 caggaagcaa acgtctatgg tgtggctatatcaggttatg aaggaagagc aggaatggct 2220 tctattattt taaaaccaaa tacatctttagatttggaaa aagtttatga acaagttgta 2280 acatttctac cagcttatgc ttgtccacgatttttaagaa ttcaggaaaa aatggaagca 2340 acaggaacat tcaaactatt gaagcatcagttggtggaag atggatttaa tccactgaaa 2400 atttctgaac cactttactt catggataacttgaaaaagt cttatgttct actgaccagg 2460 gaactttatg atcaaataat gttaggggaaataaaacttt aagattttta tatctagaac 2520 tttcatatgc tttcttagga agagtgagaggggggtatat gattctttat gaaatgggga 2580 aagggagcta acattaatta tgcatgtactatatttcctt aatatgagag ataatttttt 2640 aattgcataa gaattttaat ttcttttaattgatataaac attagttgat tattcttttt 2700 atctatttgg agattcagtg cataactaagtattttcctt aatactaaag attttaaata 2760 ataaatagtg gctagcggtt tggacaatcactaaaaatgt actttctaat aagtaaaatt 2820 tctaattttg aataaaagat taaattttactgaaaaaaaa aaaaaaaaaa aaaattggcg 2880 gccgc 2885 <210> SEQ ID NO 37<211> LENGTH: 619 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400>SEQUENCE: 37 Met Leu Leu Ser Trp Leu Thr Val Leu Gly Ala Gly Met Val ValLeu 1 5 10 15 His Phe Leu Gln Lys Leu Leu Phe Pro Tyr Phe Trp Asp AspPhe Trp 20 25 30 Phe Val Leu Lys Val Val Leu Ile Ile Ile Arg Leu Lys LysTyr Glu 35 40 45 Lys Arg Gly Glu Leu Val Thr Val Leu Asp Lys Phe Leu SerHis Ala 50 55 60 Lys Arg Gln Pro Arg Lys Pro Phe Ile Ile Tyr Glu Gly AspIle Tyr 65 70 75 80 Thr Tyr Gln Asp Val Asp Lys Arg Ser Ser Arg Val AlaHis Val Phe 85 90 95 Leu Asn His Ser Ser Leu Lys Lys Gly Asp Thr Val AlaLeu Leu Met 100 105 110 Ser Asn Glu Pro Asp Phe Val His Val Trp Phe GlyLeu Ala Lys Leu 115 120 125 Gly Cys Val Val Ala Phe Leu Asn Thr Asn IleArg Ser Asn Ser Leu 130 135 140 Leu Asn Cys Ile Arg Ala Cys Gly Pro ArgAla Leu Val Val Gly Ala 145 150 155 160 Asp Leu Leu Gly Thr Val Glu GluIle Leu Pro Ser Leu Ser Glu Asn 165 170 175 Ile Ser Val Trp Gly Met LysAsp Ser Val Pro Gln Gly Val Ile Ser 180 185 190 Leu Lys Glu Lys Leu SerThr Ser Pro Asp Glu Pro Val Pro Arg Ser 195 200 205 His His Val Val SerLeu Leu Lys Ser Thr Cys Leu Tyr Ile Phe Thr 210 215 220 Ser Gly Thr ThrGly Leu Pro Lys Ala Ala Val Ile Ser Gln Leu Gln 225 230 235 240 Val LeuArg Gly Ser Ala Val Leu Trp Ala Phe Gly Cys Thr Ala His 245 250 255 AspIle Val Tyr Ile Thr Leu Pro Leu Tyr His Ser Ser Ala Ala Ile 260 265 270Leu Gly Ile Ser Gly Cys Val Glu Leu Gly Ala Thr Cys Val Leu Lys 275 280285 Lys Lys Phe Ser Ala Ser Gln Phe Trp Ser Asp Cys Lys Lys Tyr Asp 290295 300 Val Thr Val Phe Gln Tyr Ile Gly Glu Leu Cys Arg Tyr Leu Cys Lys305 310 315 320 Gln Ser Lys Arg Glu Gly Glu Lys Asp His Lys Val Arg LeuAla Ile 325 330 335 Gly Asn Gly Ile Arg Ser Asp Val Trp Arg Glu Phe LeuAsp Arg Phe 340 345 350 Gly Asn Ile Lys Val Cys Glu Leu Tyr Ala Ala ThrGlu Ser Ser Ile 355 360 365 Ser Phe Met Asn Tyr Thr Gly Arg Ile Gly AlaIle Gly Arg Thr Asn 370 375 380 Leu Phe Tyr Lys Leu Leu Ser Thr Phe AspLeu Ile Lys Tyr Asp Phe 385 390 395 400 Gln Lys Asp Glu Pro Met Arg AsnGlu Gln Gly Trp Cys Ile His Val 405 410 415 Lys Lys Gly Glu Pro Gly LeuLeu Ile Ser Arg Val Asn Ala Lys Asn 420 425 430 Pro Phe Phe Gly Tyr AlaGly Pro Tyr Lys His Thr Lys Asp Lys Leu 435 440 445 Leu Cys Asp Val PheLys Lys Gly Asp Val Tyr Leu Asn Thr Gly Asp 450 455 460 Leu Ile Val GlnAsp Gln Asp Asn Phe Leu Tyr Phe Trp Asp Arg Thr 465 470 475 480 Gly AspThr Phe Arg Trp Lys Gly Glu Asn Val Ala Thr Thr Glu Val 485 490 495 AlaAsp Val Ile Gly Met Leu Asp Phe Ile Gln Glu Ala Asn Val Tyr 500 505 510Gly Val Ala Ile Ser Gly Tyr Glu Gly Arg Ala Gly Met Ala Ser Ile 515 520525 Ile Leu Lys Pro Asn Thr Ser Leu Asp Leu Glu Lys Val Tyr Glu Gln 530535 540 Val Val Thr Phe Leu Pro Ala Tyr Ala Cys Pro Arg Phe Leu Arg Ile545 550 555 560 Gln Glu Lys Met Glu Ala Thr Gly Thr Phe Lys Leu Leu LysHis Gln 565 570 575 Leu Val Glu Asp Gly Phe Asn Pro Leu Lys Ile Ser GluPro Leu Tyr 580 585 590 Phe Met Asp Asn Leu Lys Lys Ser Tyr Val Leu LeuThr Arg Glu Leu 595 600 605 Tyr Asp Gln Ile Met Leu Gly Glu Ile Lys Leu610 615 <210> SEQ ID NO 38 <211> LENGTH: 646 <212> TYPE: PRT <213>ORGANISM: Homo sapiens <400> SEQUENCE: 38 Met Arg Ala Pro Gly Ala GlyAla Ala Ser Val Val Ser Leu Ala Leu 1 5 10 15 Leu Trp Leu Leu Gly LeuPro Trp Thr Trp Ser Ala Ala Ala Ala Leu 20 25 30 Gly Val Tyr Val Gly SerGly Gly Trp Arg Phe Leu Arg Ile Val Cys 35 40 45 Lys Thr Ala Arg Arg AspLeu Phe Gly Leu Ser Val Leu Ile Arg Val 50 55 60 Arg Leu Glu Leu Arg ArgHis Gln Arg Ala Gly His Thr Ile Pro Arg 65 70 75 80 Ile Phe Gln Ala ValVal Gln Arg Gln Pro Glu Arg Leu Ala Leu Val 85 90 95 Asp Ala Gly Thr GlyGlu Cys Trp Thr Phe Ala Gln Leu Asp Ala Tyr 100 105 110 Ser Asn Ala ValAla Asn Leu Phe Arg Gln Leu Gly Phe Ala Pro Gly 115 120 125 Asp Val ValAla Ile Phe Leu Glu Gly Arg Pro Glu Phe Val Gly Leu 130 135 140 Trp LeuGly Leu Ala Lys Ala Gly Met Glu Ala Ala Leu Leu Asn Val 145 150 155 160Asn Leu Arg Arg Glu Pro Leu Ala Phe Cys Leu Gly Thr Ser Gly Ala 165 170175 Lys Ala Leu Ile Phe Gly Gly Glu Met Val Ala Ala Val Ala Glu Val 180185 190 Ser Gly His Leu Gly Lys Ser Leu Ile Lys Phe Cys Ser Gly Asp Leu195 200 205 Gly Pro Glu Gly Ile Leu Pro Asp Thr His Leu Leu Asp Pro LeuLeu 210 215 220 Lys Glu Ala Ser Thr Ala Pro Leu Ala Gln Ile Pro Ser LysGly Met 225 230 235 240 Asp Asp Arg Leu Phe Tyr Ile Tyr Thr Ser Gly ThrThr Gly Leu Pro 245 250 255 Lys Ala Ala Ile Val Val His Ser Arg Tyr TyrArg Met Ala Ala Phe 260 265 270 Gly His His Ala Tyr Arg Met Gln Ala AlaAsp Val Leu Tyr Asp Cys 275 280 285 Leu Pro Leu Tyr His Ser Ala Gly AsnIle Ile Gly Val Gly Gln Cys 290 295 300 Leu Ile Tyr Gly Leu Thr Val ValLeu Arg Lys Lys Phe Ser Ala Ser 305 310 315 320 Arg Phe Trp Asp Asp CysIle Lys Tyr Asn Cys Thr Val Val Gln Tyr 325 330 335 Ile Gly Glu Ile CysArg Tyr Leu Leu Lys Gln Pro Val Arg Glu Ala 340 345 350 Glu Arg Arg HisArg Val Arg Leu Ala Val Gly Asn Gly Leu Arg Pro 355 360 365 Ala Ile TrpGlu Glu Phe Thr Glu Arg Phe Gly Val Arg Gln Ile Gly 370 375 380 Glu PheTyr Gly Ala Thr Glu Cys Asn Cys Ser Ile Ala Asn Met Asp 385 390 395 400Gly Lys Val Gly Ser Cys Gly Phe Asn Ser Arg Ile Leu Pro His Val 405 410415 Tyr Pro Ile Arg Leu Val Lys Val Asn Glu Asp Thr Met Glu Leu Leu 420425 430 Arg Asp Ala Gln Gly Leu Cys Ile Pro Cys Gln Ala Gly Glu Pro Gly435 440 445 Leu Leu Val Gly Gln Ile Asn Gln Gln Asp Pro Leu Arg Arg PheAsp 450 455 460 Gly Tyr Val Ser Glu Ser Ala Thr Ser Lys Lys Ile Ala HisSer Val 465 470 475 480 Phe Ser Lys Gly Asp Ser Ala Tyr Leu Ser Gly AspVal Leu Val Met 485 490 495 Asp Glu Leu Gly Tyr Met Tyr Phe Arg Asp ArgSer Gly Asp Thr Phe 500 505 510 Arg Trp Arg Gly Glu Asn Val Ser Thr ThrGlu Val Glu Gly Val Leu 515 520 525 Ser Arg Leu Leu Gly Gln Thr Asp ValAla Val Tyr Gly Val Ala Val 530 535 540 Pro Gly Val Glu Gly Lys Ala GlyMet Ala Ala Val Ala Asp Pro His 545 550 555 560 Ser Leu Leu Asp Pro AsnAla Ile Tyr Gln Glu Leu Gln Lys Val Leu 565 570 575 Ala Pro Tyr Ala ArgPro Ile Phe Leu Arg Leu Leu Pro Gln Val Asp 580 585 590 Thr Thr Gly ThrPhe Lys Ile Gln Lys Thr Arg Leu Gln Arg Glu Gly 595 600 605 Phe Asp ProArg Gln Thr Ser Asp Arg Leu Phe Phe Leu Asp Leu Lys 610 615 620 Gln GlyHis Tyr Leu Pro Leu Asn Glu Ala Val Tyr Thr Arg Ile Cys 625 630 635 640Ser Gly Ala Phe Ala Leu 645 <210> SEQ ID NO 39 <211> LENGTH: 632 <212>TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 39 Leu Phe SerLys Leu Val Leu Lys Leu Pro Trp Thr Gln Val Gly Phe 1 5 10 15 Ser LeuLeu Phe Leu Tyr Leu Gly Ser Gly Gly Trp Arg Phe Ile Arg 20 25 30 Val PheIle Lys Thr Ile Arg Arg Asp Ile Phe Gly Gly Leu Val Leu 35 40 45 Leu LysVal Lys Ala Lys Val Arg Gln Cys Leu Gln Glu Arg Arg Thr 50 55 60 Val ProIle Leu Phe Ala Ser Thr Val Arg Arg His Pro Asp Lys Thr 65 70 75 80 AlaLeu Ile Phe Glu Gly Thr Asp Thr His Trp Thr Phe Arg Gln Leu 85 90 95 AspGlu Tyr Ser Ser Ser Val Ala Asn Phe Leu Gln Ala Arg Gly Leu 100 105 110Ala Ser Gly Asp Val Ala Ala Ile Phe Met Glu Asn Arg Asn Glu Phe 115 120125 Val Gly Leu Trp Leu Gly Met Ala Lys Leu Gly Val Glu Ala Ala Leu 130135 140 Ile Asn Thr Asn Leu Arg Arg Asp Ala Leu Leu His Cys Leu Thr Thr145 150 155 160 Ser Arg Ala Arg Ala Leu Val Phe Gly Ser Glu Met Ala SerAla Ile 165 170 175 Cys Glu Val His Ala Ser Leu Asp Pro Ser Leu Ser LeuPhe Cys Ser 180 185 190 Gly Ser Trp Glu Pro Gly Ala Val Pro Pro Ser ThrGlu His Leu Asp 195 200 205 Pro Leu Leu Lys Asp Ala Pro Lys His Leu ProSer Cys Pro Asp Lys 210 215 220 Gly Phe Thr Asp Lys Leu Phe Tyr Ile TyrThr Ser Gly Thr Thr Gly 225 230 235 240 Leu Pro Lys Ala Ala Ile Val ValHis Ser Arg Tyr Tyr Arg Met Ala 245 250 255 Ala Leu Val Tyr Tyr Gly PheArg Met Arg Pro Asn Asp Ile Val Tyr 260 265 270 Asp Cys Leu Pro Leu TyrHis Ser Ala Gly Asn Ile Val Gly Ile Gly 275 280 285 Gln Cys Leu Leu HisGly Met Thr Val Val Ile Arg Lys Lys Phe Ser 290 295 300 Ala Ser Arg PheTrp Asp Asp Cys Ile Lys Tyr Asn Cys Thr Ile Val 305 310 315 320 Gln TyrIle Gly Glu Leu Cys Arg Tyr Leu Leu Asn Gln Pro Pro Arg 325 330 335 GluAla Glu Asn Gln His Gln Val Arg Met Ala Leu Gly Asn Gly Leu 340 345 350Arg Gln Ser Ile Trp Thr Asn Phe Ser Ser Arg Phe His Ile Pro Gln 355 360365 Val Ala Glu Phe Tyr Gly Ala Thr Glu Cys Asn Cys Ser Leu Gly Asn 370375 380 Phe Asp Ser Gln Val Gly Ala Cys Gly Phe Asn Ser Arg Ile Leu Ser385 390 395 400 Phe Val Tyr Pro Ile Arg Leu Val Arg Val Asn Glu Asp ThrMet Glu 405 410 415 Leu Ile Arg Gly Pro Asp Gly Val Cys Ile Pro Cys GlnPro Gly Glu 420 425 430 Pro Gly Gln Leu Val Gly Arg Ile Ile Gln Lys AspPro Leu Arg Arg 435 440 445 Phe Asp Gly Tyr Leu Asn Gln Gly Ala Asn AsnLys Lys Ile Ala Lys 450 455 460 Asp Val Phe Lys Lys Gly Asp Gln Ala TyrLeu Thr Gly Asp Val Leu 465 470 475 480 Val Met Asp Glu Leu Gly Tyr LeuTyr Phe Arg Asp Arg Thr Gly Asp 485 490 495 Thr Phe Arg Trp Lys Gly GluAsn Val Ser Thr Thr Glu Val Glu Gly 500 505 510 Thr Leu Ser Arg Leu LeuAsp Met Ala Asp Val Ala Val Tyr Gly Val 515 520 525 Glu Val Pro Gly ThrGlu Gly Arg Ala Gly Met Ala Ala Val Ala Ser 530 535 540 Pro Thr Gly AsnCys Asp Leu Glu Arg Phe Ala Gln Val Leu Glu Lys 545 550 555 560 Glu LeuPro Leu Tyr Ala Arg Pro Ile Phe Leu Arg Leu Leu Pro Glu 565 570 575 LeuHis Lys Thr Gly Thr Tyr Lys Phe Gln Lys Thr Glu Leu Arg Lys 580 585 590Glu Gly Phe Asp Pro Ala Ile Val Lys Asp Pro Leu Phe Tyr Leu Asp 595 600605 Ala Gln Lys Gly Arg Tyr Val Pro Leu Asp Gln Glu Ala Tyr Ser Arg 610615 620 Ile Gln Ala Gly Glu Glu Lys Leu 625 630 <210> SEQ ID NO 40 <211>LENGTH: 619 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:40 Met Leu Leu Ser Trp Leu Thr Val Leu Gly Ala Gly Met Val Val Leu 1 510 15 His Phe Leu Gln Lys Leu Leu Phe Pro Tyr Phe Trp Asp Asp Phe Trp 2025 30 Phe Val Leu Lys Val Val Leu Ile Ile Ile Arg Leu Lys Lys Tyr Glu 3540 45 Lys Arg Gly Glu Leu Val Thr Val Leu Asp Lys Phe Leu Ser His Ala 5055 60 Lys Arg Gln Pro Arg Lys Pro Phe Ile Ile Tyr Glu Gly Asp Ile Tyr 6570 75 80 Thr Tyr Gln Asp Val Asp Lys Arg Ser Ser Arg Val Ala His Val Phe85 90 95 Leu Asn His Ser Ser Leu Lys Lys Gly Asp Thr Val Ala Leu Leu Met100 105 110 Ser Asn Glu Pro Asp Phe Val His Val Trp Phe Gly Leu Ala LysLeu 115 120 125 Gly Cys Val Val Ala Phe Leu Asn Thr Asn Ile Arg Ser AsnSer Leu 130 135 140 Leu Asn Cys Ile Arg Ala Cys Gly Pro Arg Ala Leu ValVal Gly Ala 145 150 155 160 Asp Leu Leu Gly Thr Val Glu Glu Ile Leu ProSer Leu Ser Glu Asn 165 170 175 Ile Ser Val Trp Gly Met Lys Asp Ser ValPro Gln Gly Val Ile Ser 180 185 190 Leu Lys Glu Lys Leu Ser Thr Ser ProAsp Glu Pro Val Pro Arg Ser 195 200 205 His His Val Val Ser Leu Leu LysSer Thr Cys Leu Tyr Ile Phe Thr 210 215 220 Ser Gly Thr Thr Gly Leu ProLys Ala Ala Val Ile Ser Gln Leu Gln 225 230 235 240 Val Leu Arg Gly SerAla Val Leu Trp Ala Phe Gly Cys Thr Ala His 245 250 255 Asp Ile Val TyrIle Thr Leu Pro Leu Tyr His Ser Ser Ala Ala Ile 260 265 270 Leu Gly IleSer Gly Cys Val Glu Leu Gly Ala Thr Cys Val Leu Lys 275 280 285 Lys LysPhe Ser Ala Ser Gln Phe Trp Ser Asp Cys Lys Lys Tyr Asp 290 295 300 ValThr Val Phe Gln Tyr Ile Gly Glu Leu Cys Arg Tyr Leu Cys Lys 305 310 315320 Gln Ser Lys Arg Glu Gly Glu Lys Asp His Lys Val Arg Leu Ala Ile 325330 335 Gly Asn Gly Ile Arg Ser Asp Val Trp Arg Glu Phe Leu Asp Arg Phe340 345 350 Gly Asn Ile Lys Val Cys Glu Leu Tyr Ala Ala Thr Glu Ser SerIle 355 360 365 Ser Phe Met Asn Tyr Thr Gly Arg Ile Gly Ala Ile Gly ArgThr Asn 370 375 380 Leu Phe Tyr Lys Leu Leu Ser Thr Phe Asp Leu Ile LysTyr Asp Phe 385 390 395 400 Gln Lys Asp Glu Pro Met Arg Asn Glu Gln GlyTrp Cys Ile His Val 405 410 415 Lys Lys Gly Glu Pro Gly Leu Leu Ile SerArg Val Asn Ala Lys Asn 420 425 430 Pro Phe Phe Gly Tyr Ala Gly Pro TyrLys His Thr Lys Asp Lys Leu 435 440 445 Leu Cys Asp Val Phe Lys Lys GlyAsp Val Tyr Leu Asn Thr Gly Asp 450 455 460 Leu Ile Val Gln Asp Gln AspAsn Phe Leu Tyr Phe Trp Asp Arg Thr 465 470 475 480 Gly Asp Thr Phe ArgTrp Lys Gly Glu Asn Val Ala Thr Thr Glu Val 485 490 495 Ala Asp Val IleGly Met Leu Asp Phe Ile Gln Glu Ala Asn Val Tyr 500 505 510 Gly Val AlaIle Ser Gly Tyr Glu Gly Arg Ala Gly Met Ala Ser Ile 515 520 525 Ile LeuLys Pro Asn Thr Ser Leu Asp Leu Glu Lys Val Tyr Glu Gln 530 535 540 ValVal Thr Phe Leu Pro Ala Tyr Ala Cys Pro Arg Phe Leu Arg Ile 545 550 555560 Gln Glu Lys Met Glu Ala Thr Gly Thr Phe Lys Leu Leu Lys His Gln 565570 575 Leu Val Glu Asp Gly Phe Asn Pro Leu Lys Ile Ser Glu Pro Leu Tyr580 585 590 Phe Met Asp Asn Leu Lys Lys Ser Tyr Val Leu Leu Thr Arg GluLeu 595 600 605 Tyr Asp Gln Ile Met Leu Gly Glu Ile Lys Leu 610 615<210> SEQ ID NO 41 <211> LENGTH: 643 <212> TYPE: PRT <213> ORGANISM:Homo sapiens <400> SEQUENCE: 41 Met Leu Leu Gly Ala Ser Leu Val Gly ValLeu Leu Phe Ser Lys Leu 1 5 10 15 Val Leu Lys Leu Pro Trp Thr Gln ValGly Phe Ser Leu Leu Phe Leu 20 25 30 Tyr Leu Gly Ser Gly Gly Trp Arg PheIle Arg Val Phe Ile Lys Thr 35 40 45 Ile Arg Arg Asp Ile Phe Gly Gly LeuVal Leu Leu Lys Val Lys Ala 50 55 60 Lys Val Arg Gln Cys Leu Gln Glu ArgArg Thr Val Pro Ile Leu Phe 65 70 75 80 Ala Ser Thr Val Arg Arg His ProAsp Lys Thr Ala Leu Ile Phe Glu 85 90 95 Gly Thr Asp Thr His Trp Thr PheArg Gln Leu Asp Glu Tyr Ser Ser 100 105 110 Ser Val Ala Asn Phe Leu GlnAla Arg Gly Leu Ala Ser Gly Asp Val 115 120 125 Ala Ala Ile Phe Met GluAsn Arg Asn Glu Phe Val Gly Leu Trp Leu 130 135 140 Gly Met Ala Lys LeuGly Val Glu Ala Ala Leu Ile Asn Thr Asn Leu 145 150 155 160 Arg Arg AspAla Leu Leu His Cys Leu Thr Thr Ser Arg Ala Arg Ala 165 170 175 Leu ValPhe Gly Ser Glu Met Ala Ser Ala Ile Cys Glu Val His Ala 180 185 190 SerLeu Asp Pro Ser Leu Ser Leu Phe Cys Ser Gly Ser Trp Glu Pro 195 200 205Gly Ala Val Pro Pro Ser Thr Glu His Leu Asp Pro Leu Leu Lys Asp 210 215220 Ala Pro Lys His Leu Pro Ser Cys Pro Asp Lys Gly Phe Thr Asp Lys 225230 235 240 Leu Phe Tyr Ile Tyr Thr Ser Gly Thr Thr Gly Leu Pro Lys AlaAla 245 250 255 Ile Val Val His Ser Arg Tyr Tyr Arg Met Ala Ala Leu ValTyr Tyr 260 265 270 Gly Phe Arg Met Arg Pro Asn Asp Ile Val Tyr Asp CysLeu Pro Leu 275 280 285 Tyr His Ser Ala Gly Asn Ile Val Gly Ile Gly GlnCys Leu Leu His 290 295 300 Gly Met Thr Val Val Ile Arg Lys Lys Phe SerAla Ser Arg Phe Trp 305 310 315 320 Asp Asp Cys Ile Lys Tyr Asn Cys ThrIle Val Gln Tyr Ile Gly Glu 325 330 335 Leu Cys Arg Tyr Leu Leu Asn GlnPro Pro Arg Glu Ala Glu Asn Gln 340 345 350 His Gln Val Arg Met Ala LeuGly Asn Gly Leu Arg Gln Ser Ile Trp 355 360 365 Thr Asn Phe Ser Ser ArgPhe His Ile Pro Gln Val Ala Glu Phe Tyr 370 375 380 Gly Ala Thr Glu CysAsn Cys Ser Leu Gly Asn Phe Asp Ser Gln Val 385 390 395 400 Gly Ala CysGly Phe Asn Ser Arg Ile Leu Ser Phe Val Tyr Pro Ile 405 410 415 Arg LeuVal Arg Val Asn Glu Asp Thr Met Glu Leu Ile Arg Gly Pro 420 425 430 AspGly Val Cys Ile Pro Cys Gln Pro Gly Glu Pro Gly Gln Leu Val 435 440 445Gly Arg Ile Ile Gln Lys Asp Pro Leu Arg Arg Phe Asp Gly Tyr Leu 450 455460 Asn Gln Gly Ala Asn Asn Lys Lys Ile Ala Lys Asp Val Phe Lys Lys 465470 475 480 Gly Asp Gln Ala Tyr Leu Thr Gly Asp Val Leu Val Met Asp GluLeu 485 490 495 Gly Tyr Leu Tyr Phe Arg Asp Arg Thr Gly Asp Thr Phe ArgTrp Lys 500 505 510 Gly Glu Asn Val Ser Thr Thr Glu Val Glu Gly Thr LeuSer Arg Leu 515 520 525 Leu Asp Met Ala Asp Val Ala Val Tyr Gly Val GluVal Pro Gly Thr 530 535 540 Glu Gly Arg Ala Gly Met Ala Ala Val Ala SerPro Thr Gly Asn Cys 545 550 555 560 Asp Leu Glu Arg Phe Ala Gln Val LeuGlu Lys Glu Leu Pro Leu Tyr 565 570 575 Ala Arg Pro Ile Phe Leu Arg LeuLeu Pro Glu Leu His Lys Thr Gly 580 585 590 Thr Tyr Lys Phe Gln Lys ThrGlu Leu Arg Lys Glu Gly Phe Asp Pro 595 600 605 Ala Ile Val Lys Asp ProLeu Phe Tyr Leu Asp Ala Gln Lys Gly Arg 610 615 620 Tyr Val Pro Leu AspGln Glu Ala Tyr Ser Arg Ile Gln Ala Gly Glu 625 630 635 640 Glu Lys Leu<210> SEQ ID NO 42 <211> LENGTH: 643 <212> TYPE: PRT <213> ORGANISM: Musmusculus <220> FEATURE: <221> NAME/KEY: VARIANT <222> LOCATION:(1)...(643) <223> OTHER INFORMATION: Xaa = Any Amino Acid <220> FEATURE:<221> NAME/KEY: VARIANT <222> LOCATION: 31, 144 <223> OTHER INFORMATION:Xaa = Any Amino Acid <400> SEQUENCE: 42 Met Leu Leu Gly Ala Ser Leu ValGly Val Leu Leu Phe Ser Lys Leu 1 5 10 15 Val Leu Lys Leu Pro Trp ThrGln Val Gly Phe Ser Leu Leu Xaa Leu 20 25 30 Tyr Leu Gly Ser Gly Gly TrpArg Phe Ile Arg Val Phe Ile Lys Thr 35 40 45 Val Arg Arg Asp Ile Phe GlyGly Met Val Leu Leu Lys Val Lys Thr 50 55 60 Lys Val Arg Arg Tyr Leu GlnGlu Arg Lys Thr Val Pro Leu Leu Phe 65 70 75 80 Ala Ser Met Val Gln ArgHis Pro Asp Lys Thr Ala Leu Ile Phe Glu 85 90 95 Gly Thr Asp Thr His TrpThr Phe Arg Gln Leu Asp Glu Tyr Ser Ser 100 105 110 Ser Val Ala Asn PheLeu Gln Ala Arg Gly Leu Ala Ser Gly Asn Val 115 120 125 Val Ala Leu PheMet Glu Asn Arg Asn Glu Phe Val Gly Leu Trp Xaa 130 135 140 Gly Met AlaLys Leu Gly Val Glu Ala Ala Leu Ile Asn Thr Asn Leu 145 150 155 160 ArgArg Asp Ala Leu Arg His Cys Leu Asp Thr Ser Lys Ala Arg Ala 165 170 175Leu Ile Phe Gly Ser Glu Met Ala Ser Ala Ile Cys Glu Ile His Ala 180 185190 Ser Leu Gly Pro Thr Leu Ser Leu Phe Cys Ser Gly Ser Trp Glu Pro 195200 205 Ser Thr Val Pro Val Ser Thr Glu His Leu Asp Pro Leu Leu Glu Asp210 215 220 Ala Pro Lys His Leu Pro Ser His Pro Asp Lys Gly Phe Thr AspLys 225 230 235 240 Leu Phe Tyr Ile Tyr Thr Ser Gly Thr Thr Gly Leu ProLys Ala Ala 245 250 255 Ile Val Val His Ser Arg Tyr Tyr Arg Met Ala SerLeu Val Tyr Tyr 260 265 270 Gly Phe Arg Met Arg Pro Asp Asp Ile Val TyrAsp Cys Leu Pro Leu 275 280 285 Tyr His Ser Ser Arg Lys His Arg Gly AspTrp Gln Cys Leu Leu His 290 295 300 Gly Met Thr Val Val Ile Arg Lys LysPhe Ser Ala Ser Arg Phe Trp 305 310 315 320 Asp Asp Cys Ile Lys Tyr AsnCys Thr Ile Val Gln Tyr Ile Gly Glu 325 330 335 Leu Cys Arg Tyr Leu LeuAsn Gln Pro Pro Arg Glu Ala Glu Ser Arg 340 345 350 His Lys Val Arg MetAla Leu Gly Asn Gly Leu Arg Gln Ser Ile Trp 355 360 365 Thr Asp Phe SerSer Arg Phe His Ile Pro Gln Val Ala Glu Phe Tyr 370 375 380 Gly Ala ThrGlu Cys Asn Cys Ser Leu Gly Asn Phe Asp Ser Arg Val 385 390 395 400 GlyAla Cys Gly Phe Asn Ser Arg Ile Leu Ser Phe Val Tyr Pro Ile 405 410 415Arg Leu Val Arg Val Asn Glu Asp Thr Met Glu Leu Ile Arg Gly Pro 420 425430 Asp Gly Val Cys Ile Pro Cys Gln Pro Gly Gln Pro Gly Gln Leu Val 435440 445 Gly Arg Ile Ile Gln Lys Asp Pro Leu Arg Arg Phe Asp Gly Tyr Leu450 455 460 Asn Gln Gly Ala Asn Asn Lys Lys Ile Ala Asn Asp Val Phe LysLys 465 470 475 480 Gly Asp Gln Ala Tyr Leu Thr Gly Asp Val Leu Val MetAsp Glu Leu 485 490 495 Gly Tyr Leu Tyr Phe Arg Asp Arg Thr Gly Asp ThrPhe Arg Trp Lys 500 505 510 Gly Glu Asn Val Ser Thr Thr Glu Val Glu GlyThr Leu Ser Arg Leu 515 520 525 Leu His Met Ala Asp Val Ala Val Tyr GlyVal Glu Val Pro Gly Thr 530 535 540 Glu Gly Arg Ala Gly Met Ala Ala ValAla Ser Pro Ile Ser Asn Cys 545 550 555 560 Asp Leu Glu Ser Phe Ala GlnThr Leu Lys Lys Glu Leu Pro Leu Tyr 565 570 575 Ala Arg Pro Ile Phe LeuArg Phe Leu Pro Glu Leu His Lys Thr Gly 580 585 590 Thr Phe Lys Phe GlnLys Thr Glu Leu Arg Lys Glu Gly Phe Asp Pro 595 600 605 Ser Val Val LysAsp Pro Leu Phe Tyr Leu Asp Ala Arg Lys Gly Cys 610 615 620 Tyr Val AlaLeu Asp Gln Glu Ala Tyr Thr Arg Ile Gln Ala Gly Glu 625 630 635 640 GluLys Leu <210> SEQ ID NO 43 <211> LENGTH: 630 <212> TYPE: PRT <213>ORGANISM: Homo sapiens <400> SEQUENCE: 43 Met Arg Ala Pro Gly Ala GlyAla Ala Ser Val Val Ser Leu Ala Leu 1 5 10 15 Leu Trp Leu Leu Gly LeuPro Trp Thr Trp Ser Ala Ala Ala Ala Leu 20 25 30 Gly Val Tyr Val Gly SerGly Gly Trp Arg Phe Leu Arg Ile Val Cys 35 40 45 Lys Thr Ala Arg Arg AspLeu Phe Gly Leu Ser Val Leu Ile Arg Val 50 55 60 Arg Leu Glu Leu Arg ArgHis Gln Arg Ala Gly His Thr Ile Pro Arg 65 70 75 80 Ile Phe Gln Ala ValVal Gln Arg Gln Pro Glu Arg Leu Ala Leu Val 85 90 95 Asp Ala Gly Thr GlyGlu Cys Trp Thr Phe Ala Gln Leu Asp Ala Tyr 100 105 110 Ser Asn Ala ValAla Asn Leu Phe Arg Gln Leu Gly Phe Ala Pro Gly 115 120 125 Asp Val ValAla Ile Phe Leu Glu Gly Arg Pro Glu Phe Val Gly Leu 130 135 140 Trp LeuGly Leu Ala Lys Ala Gly Met Glu Ala Ala Leu Leu Asn Val 145 150 155 160Asn Leu Arg Arg Glu Pro Leu Ala Phe Cys Leu Gly Thr Ser Gly Ala 165 170175 Ser Gly His Leu Gly Lys Ser Leu Ile Lys Phe Cys Ser Gly Asp Leu 180185 190 Gly Pro Glu Gly Ile Leu Pro Asp Thr His Leu Leu Asp Pro Leu Leu195 200 205 Lys Glu Ala Ser Thr Ala Pro Leu Ala Gln Ile Pro Ser Lys GlyMet 210 215 220 Asp Asp Arg Leu Phe Tyr Ile Tyr Thr Ser Gly Thr Thr GlyLeu Pro 225 230 235 240 Lys Ala Ala Ile Val Val His Ser Arg Tyr Tyr ArgMet Ala Ala Phe 245 250 255 Gly His His Ala Tyr Arg Met Gln Ala Ala AspVal Leu Tyr Asp Cys 260 265 270 Leu Pro Leu Tyr His Ser Ala Gly Asn IleIle Gly Val Gly Gln Cys 275 280 285 Leu Ile Tyr Gly Leu Thr Val Val LeuArg Lys Lys Phe Ser Ala Ser 290 295 300 Arg Phe Trp Asp Asp Cys Ile LysTyr Asn Cys Thr Val Val Gln Tyr 305 310 315 320 Ile Gly Glu Ile Cys ArgTyr Leu Leu Lys Gln Pro Val Arg Glu Ala 325 330 335 Glu Arg Arg His ArgVal Arg Leu Ala Val Gly Asn Gly Leu Arg Pro 340 345 350 Ala Ile Trp GluGlu Phe Thr Glu Arg Phe Gly Val Arg Gln Ile Gly 355 360 365 Glu Phe TyrGly Ala Thr Glu Cys Asn Cys Ser Ile Ala Asn Met Asp 370 375 380 Gly LysVal Gly Ser Cys Gly Phe Asn Ser Arg Ile Leu Pro His Val 385 390 395 400Tyr Pro Ile Arg Leu Val Lys Val Asn Glu Asp Thr Met Glu Leu Leu 405 410415 Arg Asp Ala Gln Gly Leu Cys Ile Pro Cys Gln Ala Gly Glu Pro Gly 420425 430 Leu Leu Val Gly Gln Ile Asn Gln Gln Asp Pro Leu Arg Arg Phe Asp435 440 445 Gly Tyr Val Ser Glu Ser Ala Thr Ser Lys Lys Ile Ala His SerVal 450 455 460 Phe Ser Lys Gly Asp Ser Ala Tyr Leu Ser Gly Asp Val LeuVal Met 465 470 475 480 Asp Glu Leu Gly Tyr Met Tyr Phe Arg Asp Arg SerGly Asp Thr Phe 485 490 495 Arg Trp Arg Gly Glu Asn Val Ser Thr Thr GluVal Glu Gly Val Leu 500 505 510 Ser Arg Leu Leu Gly Gln Thr Asp Val AlaVal Tyr Gly Val Ala Val 515 520 525 Pro Gly Val Glu Gly Lys Ala Gly MetAla Ala Val Ala Asp Pro His 530 535 540 Ser Leu Leu Asp Pro Asn Ala IleTyr Gln Glu Leu Gln Lys Val Leu 545 550 555 560 Ala Pro Tyr Ala Arg ProIle Phe Leu Arg Leu Leu Pro Gln Val Asp 565 570 575 Thr Thr Gly Thr PheLys Ile Gln Lys Thr Arg Leu Gln Arg Glu Gly 580 585 590 Phe Asp Pro ArgGln Thr Ser Asp Arg Leu Phe Phe Leu Asp Leu Lys 595 600 605 Gln Gly HisTyr Leu Pro Leu Asn Glu Ala Val Tyr Thr Arg Ile Cys 610 615 620 Ser GlyAla Phe Ala Leu 625 630 <210> SEQ ID NO 44 <211> LENGTH: 2710 <212>TYPE: DNA <213> ORGANISM: Mus musculus <400> SEQUENCE: 44 atgctgcttggagcctctct ggtgggggcg ctacttgggt ccaagctagt gctgaagctg 60 ccctggacccaggtgggatt ctccctgttg ctcctgtact tggggtctgg tggctggcgt 120 ttcatccgggtcttcatcaa gacggtcagg agagatatct ttggtggcat ggtgctcctg 180 aaggtgaagaccaaggtgcg acggtacctt caggagcgga agacggtgcc cctgctgttt 240 gcttcaatggtacagcgcca cccggacaag acagccctga ttttcgaggg cacagacact 300 cactggaccttccgccagct ggatgagtac tccagtagtg tggccaactt cctgcaggcc 360 cggggcctggcctcaggcaa tgtagttgcc ctctttatgg aaaaccgcaa tgagtttgtg 420 ggtctgtggctaggcatggc caagctgggc gtggaggcgg ctctcatcaa caccaacctt 480 aggcgggatgccctgcgcca ctgtcttgac acctcaaagg cacgagctct catctttggc 540 agtgagatggcctcagctat ctgtgagatc catgctagcc tggagcccac actcagcctc 600 ttctgctctggatcctggga gcccagcaca gtgcccgtca gcacagagca tctggaccct 660 cttctggaagatgccccgaa gcacctgccc agtcacccag acaagggttt tacagataag 720 ctcttctacatctacacatc gggcaccacg gggctaccca aagctgccat tgtggtgcac 780 agcaggtattatcgtatggc ttccctggtg tactatggat tccgcatgcg gcctgatgac 840 attgtctatgactgcctccc cctctaccac tcaagcagga aacatcgtgg ggattggcag 900 tgcttactccacggcatgac tgtggtgatc cggaagaagt tctcagcctc ccggttctgg 960 gatgattgtatcaagtacaa ctgcacagtg gtacagtaca ttggcgagct ctgccgctac 1020 ctcctgaaccagccaccccg tgaggctgag tctcggcaca aggtgcgcat ggcactgggc 1080 aacggtctccggcagtccat ctggaccgac ttctccagcc gtttccacat cccccaggtg 1140 gctgagttctatggggccac tgaatgcaac tgtagcctgg gcaactttga cagccgggtg 1200 ggggcctgtggcttcaatag ccgcatcctg tcctttgtgt accctatccg tttggtacgt 1260 gtcaatgaggataccatgga actgatccgg ggacccgatg gagtctgcat tccctgtcaa 1320 ccaggtcagccaggccagct ggtgggtcgc atcatccagc aggaccctct gcgccgtttc 1380 gacgggtacctcaaccaggg tgccaacaac aagaagattg ctaatgatgt cttcaagaag 1440 ggggaccaagcctacctcac tggtgacgtc ctggtgatgg atgagctggg ttacctgtac 1500 ttccgagatcgcactgggga cacgttccgc tggaaagggg agaatgtatc taccactgag 1560 gtggagggcacactcagccg cctgcttcat atggcagatg tggcagttta tggtgttgag 1620 gtgccaggaactgaaggccg agcaggaatg gctgccgttg caagtcccat cagcaactgt 1680 gacctggagagctttgcaca gaccttgaaa aaggagctgc ctctgtatgc ccgccccatc 1740 ttcctgcgcttcttgcctga gctgcacaag acagggacct tcaagttcca gaagacagag 1800 ttgcggaaggagggctttga cccatctgtt gtgaaagacc cgctgttcta tctggatgct 1860 cggaagggctgctacgttgc actggaccag gaggcctata cccgcatcca ggcaggcgag 1920 gagaagctgtgatttccccc tacatccctc tgagggccag aagatgctgg attcagagcc 1980 ctagcgtccaccccagaggg tcctgggcaa tgccagacca aagctagcag ggcccgcacc 2040 tccgcccctaggtgctgatc tcccctctcc caaactgcca agtgactcac tgccgcttcc 2100 ccgaccctccagaggctttc tgtgaaagtc tcatccaagc tgtgtcttct ggtccaggcg 2160 tggcccctggccccagggtt tctgataggc tcctttagga tggtatcttg ggtccagcgg 2220 gccagggtgtgggagaggag tcactaagat ccctccaatc agaagggagc ttacaaagga 2280 accaaggcaaagcctgtaga ctcaggaagc taagtggcca gagactatag tggccagtca 2340 tcccatgtccacagaggatc ttggtccaga gctgccaaag tgtcacctct ccctgcctgc 2400 acctctggggaaaagaggac agcatgtggc cactgggcac ctgtctcaag aagtcaggat 2460 cacacactcagtccttgttt ctccaggttc ccttgttctt gtctcgggga gggagggacg 2520 agtgtcctgtctgtccttcc tgcctgtctg tgagtctgtg ttgcttctcc atctgtccta 2580 gcctgagtgtgggtggaaca ggcatgagga gagtgtggct caggggccaa taaactctgc 2640 cttgactcctcttaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 2700 aaaaaaaaaa2710 <210> SEQ ID NO 45 <211> LENGTH: 627 <212> TYPE: PRT <213>ORGANISM: Mus musculus <400> SEQUENCE: 45 Met Leu Leu Gly Ala Ser LeuVal Gly Ala Leu Leu Phe Ser Lys Leu 1 5 10 15 Val Leu Lys Leu Pro TrpThr Gln Val Gly Phe Ser Leu Leu Leu Leu 20 25 30 Tyr Leu Gly Ser Gly GlyTrp Arg Phe Ile Arg Val Phe Ile Lys Thr 35 40 45 Val Arg Arg Asp Ile PheGly Gly Met Val Leu Leu Lys Val Lys Thr 50 55 60 Lys Val Arg Arg Tyr LeuGln Glu Arg Lys Thr Val Pro Leu Leu Phe 65 70 75 80 Ala Ser Met Val GlnArg His Pro Asp Lys Thr Ala Leu Ile Phe Glu 85 90 95 Gly Thr Asp Thr HisTrp Thr Phe Arg Gln Leu Asp Glu Tyr Ser Ser 100 105 110 Ser Val Ala AsnPhe Leu Gln Ala Arg Gly Leu Ala Ser Gly Asn Val 115 120 125 Val Ala LeuPhe Met Glu Asn Arg Asn Glu Phe Val Gly Leu Trp Leu 130 135 140 Gly MetAla Lys Leu Gly Val Glu Ala Ala Leu Ile Asn Thr Asn Leu 145 150 155 160Arg Arg Asp Ala Leu Arg His Cys Leu Asp Thr Ser Lys Ala Arg Ala 165 170175 Leu Ile Phe Gly Ser Glu Met Ala Ser Ala Ile Cys Glu Ile His Ala 180185 190 Ser Leu Glu Pro Thr Leu Ser Leu Phe Cys Ser Gly Ser Trp Glu Pro195 200 205 Ser Thr Val Pro Val Ser Thr Glu His Leu Asp Pro Leu Leu GluAsp 210 215 220 Leu Phe Tyr Ile Tyr Thr Ser Gly Thr Thr Gly Leu Pro LysAla Ala 225 230 235 240 Ile Val Val His Ser Arg Tyr Tyr Arg Met Ala SerLeu Val Tyr Tyr 245 250 255 Gly Phe Arg Met Arg Pro Asp Asp Ile Val TyrAsp Cys Leu Pro Leu 260 265 270 Tyr His Ser Ser Arg Lys His Arg Gly AspTrp Gln Cys Leu Leu His 275 280 285 Gly Met Thr Val Val Ile Arg Lys LysPhe Ser Ala Ser Arg Phe Trp 290 295 300 Asp Asp Cys Ile Lys Tyr Asn CysThr Val Val Gln Tyr Ile Gly Glu 305 310 315 320 Leu Cys Arg Tyr Leu LeuAsn Gln Pro Pro Arg Glu Ala Glu Ser Arg 325 330 335 His Lys Val Arg MetAla Leu Gly Asn Gly Leu Arg Gln Ser Ile Trp 340 345 350 Thr Asp Phe SerSer Arg Phe His Ile Pro Gln Val Ala Glu Phe Tyr 355 360 365 Gly Ala ThrGlu Cys Asn Cys Ser Leu Gly Asn Phe Asp Ser Arg Val 370 375 380 Gly AlaCys Gly Phe Asn Ser Arg Ile Leu Ser Phe Val Tyr Pro Ile 385 390 395 400Arg Leu Val Arg Val Asn Glu Asp Thr Met Glu Leu Ile Arg Gly Pro 405 410415 Asp Gly Val Cys Ile Pro Cys Gln Pro Gly Gln Pro Gly Gln Leu Val 420425 430 Gly Arg Ile Ile Gln Gln Asp Pro Leu Arg Arg Phe Asp Gly Tyr Leu435 440 445 Asn Gln Gly Ala Asn Asn Lys Lys Ile Ala Asn Asp Val Phe LysLys 450 455 460 Gly Asp Gln Ala Tyr Leu Thr Gly Asp Val Leu Val Met AspGlu Leu 465 470 475 480 Gly Tyr Leu Tyr Phe Arg Asp Arg Thr Gly Asp ThrPhe Arg Trp Lys 485 490 495 Gly Glu Asn Val Ser Thr Thr Glu Val Glu GlyThr Leu Ser Arg Leu 500 505 510 Leu His Met Ala Asp Val Ala Val Tyr GlyVal Glu Val Pro Gly Thr 515 520 525 Glu Gly Arg Ala Gly Met Ala Ala ValAla Ser Pro Ile Ser Asn Cys 530 535 540 Asp Leu Glu Ser Phe Ala Gln ThrLeu Lys Lys Glu Leu Pro Leu Tyr 545 550 555 560 Ala Arg Pro Ile Phe LeuArg Phe Leu Pro Glu Leu His Lys Thr Gly 565 570 575 Thr Phe Lys Phe GlnLys Thr Glu Leu Arg Lys Glu Gly Phe Asp Pro 580 585 590 Ser Val Val LysAsp Pro Leu Phe Tyr Leu Asp Ala Arg Lys Gly Cys 595 600 605 Tyr Val AlaLeu Asp Gln Glu Ala Tyr Thr Arg Ile Gln Ala Gly Glu 610 615 620 Glu LysLeu 625 <210> SEQ ID NO 46 <211> LENGTH: 3694 <212> TYPE: DNA <213>ORGANISM: Homo sapiens <400> SEQUENCE: 46 tcgacccacg gcgtccgggaccccaaagca gaagcccgca cagtaggcac agcgcaccca 60 agaagggtcc aggagtctgcagaaacagaa aggtccccgg cctcagcctc ctagtccctg 120 cctgcctcct gcctgagcttctgggagact gaaggcacgg cttgcagctt caggatgcgg 180 gctccgggtg cgggcgcggcctcggtggtc tcgctggcgc tgttgtggct gctggggctg 240 ccgtggacct ggagcgcggcagcggcgctc ggcgtgtacg tgggcagcgg cggctggcgc 300 ttcctgcgca tcgtctgcaagaccgcgagg cgagacctct tcggtctctc tgtgctgatc 360 cgcgtgcgcc tggagctgcggcggcaccag cgtgccggcc acaccatccc gcgcatcttt 420 caggcggtag tgcagcgacagcccgagcgc ctggcgctgg tggatgccgg gaccggcgag 480 tgctggacct ttgcgcagctggacgcctac tccaatgcgg tagccaacct cttccgccag 540 ctgggcttcg cgccgggcgacgtggtggcc atcttcctgg agggccggcc ggagttcgtg 600 gggctgtggc tgggcctggccaaggcgggc atggaggccg cgctgctcaa cgtgaacctg 660 cggcgcgagc ccctggccttctgcctgggc acctcgggcg ctaaggccct gatctttgga 720 ggagaaatgg tggcggcggtggccgaagtg agcgggcatc tggggaaaag tttgatcaag 780 ttctgctctg gagacttggggcccgagggc atcttgccgg acacccacct cctggacccg 840 ctgctgaagg aggcctctactgcccccttg gcacagatcc ccagcaaggg catggacgat 900 cgtcttttct acatctacacgtcggggacc accgggctgc ccaaggctgc cattgtcgtg 960 cacagcaggt actaccgcatggcagccttc ggccaccacg cctaccgcat gcaggcggct 1020 gacgtgctct atgactgcctgcccctgtac cactcggcag gaaacatcat cggcgtgggg 1080 cagtgtctca tctatgggctgacagtcgtc ctccgcaaga aattctcggc cagccgcttc 1140 tgggacgact gcatcaagtacaactgcacg gtggttcagt acatcgggga gatctgccgc 1200 tacctgctga agcagccggtgcgcgaggcg gagaggcgac accgcgtgcg cctggcggtg 1260 gggaacgggc tgcgtcctgccatctgggag gagttcacgg agcgcttcgg cgtacgccaa 1320 atcggggagt tctacggcgccaccgagtgc aactgcagca ttgccaacat ggacggcaag 1380 gtcggctcct gtggtttcaacagccgcatc ctgccccacg tgtaccccat ccggctggtg 1440 aaggtcaatg aggacacaatggagctgctg cgggatgccc agggcctctg catcccctgc 1500 caggccgggg agcctggcctccttgtgggt cagatcaacc aacaggaccc gctgcgccgc 1560 ttcgatggct atgtcagcgagagcgccacc agcaagaaga tcgcccacag cgtcttcagc 1620 aagggcgaca gcgcctacctctcaggtgac gtgctagtga tggatgagct gggctacatg 1680 tacttccggg accgtagcggggacaccttc cgctggcgag gggagaacgt ctccaccacc 1740 gaggtggagg gcgtgctgagccgcctgctg ggccagacag acgtggccgt ctatggggtg 1800 gctgttccag gagtggagggtaaggcaggg atggcggccg tcgcagaccc ccacagcctg 1860 ctggacccca acgcgatataccaggagctg cagaaggtgc tggcacccta tgcccggccc 1920 atcttcctgc gcctcctgccccaggtggac accacaggca ccttcaagat ccagaagacg 1980 aggctgcagc gagagggctttgacccacgc cagacctcag accggctctt cttcctggac 2040 ctgaagcagg gccactacctgcccttaaat gaggcagtct acactcgcat ctgctcgggc 2100 gccttcgccc tctgaagctgttcctctact ggccacaaac tctgggcctg gtgggagagg 2160 ccagcttgag ccagacagcgctgcccaggg gtggccgcct agtacacacc cacctggccg 2220 agctgtacct ggcacggcccatcctggact gagaaactgg aacctcagag gaacccgtgc 2280 ctctctgctg ccttggtgcccctgtgtctg cctcctctcc ctgcttttca gcctctgtct 2340 ccttccatcc ctgtccctgtctggccttaa ctcttccctc tctttctttt ctttctttct 2400 ttcttttttt ttaagatagagtctcactct gctgcccggg ctagagtgca gtggtgggat 2460 ctcggctcac tgcaacctctgcctcctggg gttcaagtga tcctcccacc tcagcctcct 2520 gagtagctgg gattacaggcacccgccacc acgtccagct aatttttata tttttagtag 2580 agacggggtt tcaccatgttggtcaggctg gtcttgaact cctgacctca ggtgatccgc 2640 tggcctcggc ctcccagagtgctgggatta taggcgtgag cctctggccc ggcctttcct 2700 ttttcctctc ctctcctgccgagagtggaa cacacgtgtc ctgggagctg catcttgtgt 2760 agggtccagc tgcttttggggactgcagga atcatctccc ctgggccctg gactcggact 2820 ggggcctccc cacctccctctcggctgtgc cttacggagc cccaatccag gcctcctgtg 2880 gctgttgggt tccagatgctgcagctccat gtgacttcca agcaggccct ccgccctccc 2940 tgctgaatgg aggagccgggggtcccccag gccaactgga aaatctccca ggctaggcca 3000 attgcctttt gcacttccccgttcctgtca catttcccca gccccacctt cccctcctga 3060 tgccctgaaa gcttccggaattgactgtga ccacttggat gtcaccactg tcagcccctg 3120 ccttgatgtc cccatttagccatctccatg gagctcctgc tggagggccc tgaaccctgc 3180 actgcgtggc tgcccagccagctgcctcct gtcctgggag gaggcctcct gggtgtcctc 3240 atctggtgtg tctactggagggtcccacag gagaggcagc agaggggtca ggggaggtct 3300 cctgccgggg gttggcctctcaagcctcag gggttctagc ctgttgaata taccccacct 3360 ggtgggtggc ccctccgatgtccccactga tggctctgac accgtgttgg tggcgatgtc 3420 ccagacaatc ccaccaggacggcccagaca tccctactgg cttcgctggt ggctcatctc 3480 gaacatccac gccagcctttctggggccgg ccacccaggc cgcctgtccg tctgtcctcc 3540 ctccagcagc accccctggcccctggagtg gtggggccat ggcaagagac accgtggcgt 3600 ctcatgtgaa ctttcctgggcactgtggtt ttatttccta attgatttaa gaaataaacc 3660 tgaagaccgt ctggtgaaaaaaaaaaaaaa aaaa 3694 <210> SEQ ID NO 47 <211> LENGTH: 646 <212> TYPE:PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 47 Met Arg Ala Pro GlyAla Gly Ala Ala Ser Val Val Ser Leu Ala Leu 1 5 10 15 Leu Trp Leu LeuGly Leu Pro Trp Thr Trp Ser Ala Ala Ala Ala Leu 20 25 30 Gly Val Tyr ValGly Ser Gly Gly Trp Arg Phe Leu Arg Ile Val Cys 35 40 45 Lys Thr Ala ArgArg Asp Leu Phe Gly Leu Ser Val Leu Ile Arg Val 50 55 60 Arg Leu Glu LeuArg Arg His Gln Arg Ala Gly His Thr Ile Pro Arg 65 70 75 80 Ile Phe GlnAla Val Val Gln Arg Gln Pro Glu Arg Leu Ala Leu Val 85 90 95 Asp Ala GlyThr Gly Glu Cys Trp Thr Phe Ala Gln Leu Asp Ala Tyr 100 105 110 Ser AsnAla Val Ala Asn Leu Phe Arg Gln Leu Gly Phe Ala Pro Gly 115 120 125 AspVal Val Ala Ile Phe Leu Glu Gly Arg Pro Glu Phe Val Gly Leu 130 135 140Trp Leu Gly Leu Ala Lys Ala Gly Met Glu Ala Ala Leu Leu Asn Val 145 150155 160 Asn Leu Arg Arg Glu Pro Leu Ala Phe Cys Leu Gly Thr Ser Gly Ala165 170 175 Lys Ala Leu Ile Phe Gly Gly Glu Met Val Ala Ala Val Ala GluVal 180 185 190 Ser Gly His Leu Gly Lys Ser Leu Ile Lys Phe Cys Ser GlyAsp Leu 195 200 205 Gly Pro Glu Gly Ile Leu Pro Asp Thr His Leu Leu AspPro Leu Leu 210 215 220 Lys Glu Ala Ser Thr Ala Pro Leu Ala Gln Ile ProSer Lys Gly Met 225 230 235 240 Asp Asp Arg Leu Phe Tyr Ile Tyr Thr SerGly Thr Thr Gly Leu Pro 245 250 255 Lys Ala Ala Ile Val Val His Ser ArgTyr Tyr Arg Met Ala Ala Phe 260 265 270 Gly His His Ala Tyr Arg Met GlnAla Ala Asp Val Leu Tyr Asp Cys 275 280 285 Leu Pro Leu Tyr His Ser AlaGly Asn Ile Ile Gly Val Gly Gln Cys 290 295 300 Leu Ile Tyr Gly Leu ThrVal Val Leu Arg Lys Lys Phe Ser Ala Ser 305 310 315 320 Arg Phe Trp AspAsp Cys Ile Lys Tyr Asn Cys Thr Val Val Gln Tyr 325 330 335 Ile Gly GluIle Cys Arg Tyr Leu Leu Lys Gln Pro Val Arg Glu Ala 340 345 350 Glu ArgArg His Arg Val Arg Leu Ala Val Gly Asn Gly Leu Arg Pro 355 360 365 AlaIle Trp Glu Glu Phe Thr Glu Arg Phe Gly Val Arg Gln Ile Gly 370 375 380Glu Phe Tyr Gly Ala Thr Glu Cys Asn Cys Ser Ile Ala Asn Met Asp 385 390395 400 Gly Lys Val Gly Ser Cys Gly Phe Asn Ser Arg Ile Leu Pro His Val405 410 415 Tyr Pro Ile Arg Leu Val Lys Val Asn Glu Asp Thr Met Glu LeuLeu 420 425 430 Arg Asp Ala Gln Gly Leu Cys Ile Pro Cys Gln Ala Gly GluPro Gly 435 440 445 Leu Leu Val Gly Gln Ile Asn Gln Gln Asp Pro Leu ArgArg Phe Asp 450 455 460 Gly Tyr Val Ser Glu Ser Ala Thr Ser Lys Lys IleAla His Ser Val 465 470 475 480 Phe Ser Lys Gly Asp Ser Ala Tyr Leu SerGly Asp Val Leu Val Met 485 490 495 Asp Glu Leu Gly Tyr Met Tyr Phe ArgAsp Arg Ser Gly Asp Thr Phe 500 505 510 Arg Trp Arg Gly Glu Asn Val SerThr Thr Glu Val Glu Gly Val Leu 515 520 525 Ser Arg Leu Leu Gly Gln ThrAsp Val Ala Val Tyr Gly Val Ala Val 530 535 540 Pro Gly Val Glu Gly LysAla Gly Met Ala Ala Val Ala Asp Pro His 545 550 555 560 Ser Leu Leu AspPro Asn Ala Ile Tyr Gln Glu Leu Gln Lys Val Leu 565 570 575 Ala Pro TyrAla Arg Pro Ile Phe Leu Arg Leu Leu Pro Gln Val Asp 580 585 590 Thr ThrGly Thr Phe Lys Ile Gln Lys Thr Arg Leu Gln Arg Glu Gly 595 600 605 PheAsp Pro Arg Gln Thr Ser Asp Arg Leu Phe Phe Leu Asp Leu Lys 610 615 620Gln Gly His Tyr Leu Pro Leu Asn Glu Ala Val Tyr Thr Arg Ile Cys 625 630635 640 Ser Gly Ala Phe Ala Leu 645 <210> SEQ ID NO 48 <211> LENGTH:2362 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 48ggaattccaa aaaaaaaaaa tacgactaca cctgctccgg agcccgcggc ggtacctgca 60gcggaggagc tctgtcttcc ccttcatctc acgcgagccc ggcgtcccgc cgcgtgcgcc 120ccggcgcagc ccgccagtcc gcccggagcc cgcccagtcg ccgcgctgca cgcccggggt 180gaaccctctg ccctcgctgg gacagagggc cccgcagccg tcatgctttc cgccatctac 240acagtcctgg cgggactgct gttcctgccg ctcctggtga acctctgctg cccatacttc 300ttccaggaca taggctactt cttgaaggtg gccgccgtgg gccggagggt gcgcagctac 360gggcagcggc ggccggcgcg caccatcctg cgggcgttcc tggagaaagc gcgccagacg 420ccacacaagc cttttctgct cttccgcgac gagactctca cctacgcgca ggtggaccgg 480cgcagcaatc aagtggcccg ggcgctgcac gaccacctcg gcctgcgcca gggagactgc 540gtggcgctcc ttatgggtaa cgagccggcc tacgtgtggc tgtggctggg gctggtgaag 600ctgggctgtg ccatggcgtg cctcaattac aacatccgcg cgaagtccct gctgcactgc 660ttccagtgct gcggggcgaa ggtgctgctg gtgtcgccag aactacaagc agctgtcgaa 720gagatactgc caagccttaa aaaagatgat gtgtccatct attatgtgag cagaacttct 780aacacagatg ggattgactc tttcctggac aaagtggatg aagtatcaac tgaacctatc 840ccagagtcat ggaggtctga agtcactttt tccactcctg ccttatacat ttatacttct 900ggaaccacag gtcttccaaa agcagccatg atcactcatc agcgcatatg gtatggaact 960ggcctcactt ttgtaagcgg attgaaggca gatgatgtca tctatatcac tctgcccttt 1020taccacagtg ctgcactact gattggcatt cacggatgta ttgtggctgg tgctactctt 1080gccttgcgga ctaaattttc agccagccag ttttgggatg actgcagaaa atacaacgtc 1140actgtcattc agtatatcgg tgaactgctt cggtatttat gcaactcacc acagaaacca 1200aatgaccgtg atcataaagt gagactggca ctgggaaatg gcttacgagg agatgtgtgg 1260agacaatttg tcaagagatt tggggacata tgcatctatg agttctatgc tgccactgaa 1320ggcaatattg gatttatgaa ttatgcgaga aaagttggtg ctgttggaag agtaaactac 1380ctacagaaaa aaatcataac ttatgacctg attaaatatg atgtggagaa agatgaacct 1440gtccgagatg aaaatggata ttgcgtcaga gttcccaaag gtgaagttgg acttctggtt 1500tgcaaaatca cacaacttac accatttaat ggctatgctg gagcaaaggc tcagacagag 1560aagaaaaaac tgagagatgt ctttaagaaa ggagacctct atttcaacag tggagatctc 1620ttaatggttg accatgaaaa tttcatctat ttccacgaca gagttggaga tacattccgg 1680tggaaagggg aaaatgtggc caccactgaa gttgctgata cagttggact ggttgatttt 1740gtccaagaag taaatgttta tggagtgcat gtgccagatc atgagggtcg cattggcatg 1800gcctccatca aaatgaaaga aaaccatgaa tttgatggaa agaaactctt tcagcacatt 1860gctgattacc tacctagtta tgcaaggccc cggtttctaa gaatacagga caccattgag 1920atcactggaa cttttaaaca ccgcaaaatg accctggtgg aggagggctt taaccctgct 1980gtcatcaaag atgccttgta tttcttggat gacacagcaa aaatgtatgt gcctatgact 2040gaggacatct ataatgccat aagtgctaaa accctgaaac tctgaatatt cccaggagga 2100taactcaaca tttccagaaa gaaactgaat ggacagccac ttgatataat ccaactttaa 2160tttgattgaa gattgtgagg aaattttgta ggaaatttgc atacccgtaa agggagactt 2220ttttaaataa cagttgagtc tttgcaagta aaaagattta gagattatta tttttcagtg 2280tgcacctact gtttgtattt gcaaactgag cttgttggag ggaaggcatt attttttaaa 2340atacttagta aattaaatga ac 2362 <210> SEQ ID NO 49 <211> LENGTH: 620 <212>TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 49 Met Leu SerAla Ile Tyr Thr Val Leu Ala Gly Leu Leu Phe Leu Pro 1 5 10 15 Leu LeuVal Asn Leu Cys Cys Pro Tyr Phe Phe Gln Asp Ile Gly Tyr 20 25 30 Phe LeuLys Val Ala Ala Val Gly Arg Arg Val Arg Ser Tyr Gly Gln 35 40 45 Arg ArgPro Ala Arg Thr Ile Leu Arg Ala Phe Leu Glu Lys Ala Arg 50 55 60 Gln ThrPro His Lys Pro Phe Leu Leu Phe Arg Asp Glu Thr Leu Thr 65 70 75 80 TyrAla Gln Val Asp Arg Arg Ser Asn Gln Val Ala Arg Ala Leu His 85 90 95 AspHis Leu Gly Leu Arg Gln Gly Asp Cys Val Ala Leu Leu Met Gly 100 105 110Asn Glu Pro Ala Tyr Val Trp Leu Trp Leu Gly Leu Val Lys Leu Gly 115 120125 Cys Ala Met Ala Cys Leu Asn Tyr Asn Ile Arg Ala Lys Ser Leu Leu 130135 140 His Cys Phe Gln Cys Cys Gly Ala Lys Val Leu Leu Val Ser Pro Glu145 150 155 160 Leu Gln Ala Ala Val Glu Glu Ile Leu Pro Ser Leu Lys LysAsp Asp 165 170 175 Val Ser Ile Tyr Tyr Val Ser Arg Thr Ser Asn Thr AspGly Ile Asp 180 185 190 Ser Phe Leu Asp Lys Val Asp Glu Val Ser Thr GluPro Ile Pro Glu 195 200 205 Ser Trp Arg Ser Glu Val Thr Phe Ser Thr ProAla Leu Tyr Ile Tyr 210 215 220 Thr Ser Gly Thr Thr Gly Leu Pro Lys AlaAla Met Ile Thr His Gln 225 230 235 240 Arg Ile Trp Tyr Gly Thr Gly LeuThr Phe Val Ser Gly Leu Lys Ala 245 250 255 Asp Asp Val Ile Tyr Ile ThrLeu Pro Phe Tyr His Ser Ala Ala Leu 260 265 270 Leu Ile Gly Ile His GlyCys Ile Val Ala Gly Ala Thr Leu Ala Leu 275 280 285 Arg Thr Lys Phe SerAla Ser Gln Phe Trp Asp Asp Cys Arg Lys Tyr 290 295 300 Asn Val Thr ValIle Gln Tyr Ile Gly Glu Leu Leu Arg Tyr Leu Cys 305 310 315 320 Asn SerPro Gln Lys Pro Asn Asp Arg Asp His Lys Val Arg Leu Ala 325 330 335 LeuGly Asn Gly Leu Arg Gly Asp Val Trp Arg Gln Phe Val Lys Arg 340 345 350Phe Gly Asp Ile Cys Ile Tyr Glu Phe Tyr Ala Ala Thr Glu Gly Asn 355 360365 Ile Gly Phe Met Asn Tyr Ala Arg Lys Val Gly Ala Val Gly Arg Val 370375 380 Asn Tyr Leu Gln Lys Lys Ile Ile Thr Tyr Asp Leu Ile Lys Tyr Asp385 390 395 400 Val Glu Lys Asp Glu Pro Val Arg Asp Glu Asn Gly Tyr CysVal Arg 405 410 415 Val Pro Lys Gly Glu Val Gly Leu Leu Val Cys Lys IleThr Gln Leu 420 425 430 Thr Pro Phe Asn Gly Tyr Ala Gly Ala Lys Ala GlnThr Glu Lys Lys 435 440 445 Lys Leu Arg Asp Val Phe Lys Lys Gly Asp LeuTyr Phe Asn Ser Gly 450 455 460 Asp Leu Leu Met Val Asp His Glu Asn PheIle Tyr Phe His Asp Arg 465 470 475 480 Val Gly Asp Thr Phe Arg Trp LysGly Glu Asn Val Ala Thr Thr Glu 485 490 495 Val Ala Asp Thr Val Gly LeuVal Asp Phe Val Gln Glu Val Asn Val 500 505 510 Tyr Gly Val His Val ProAsp His Glu Gly Arg Ile Gly Met Ala Ser 515 520 525 Ile Lys Met Lys GluAsn His Glu Phe Asp Gly Lys Lys Leu Phe Gln 530 535 540 His Ile Ala AspTyr Leu Pro Ser Tyr Ala Arg Pro Arg Phe Leu Arg 545 550 555 560 Ile GlnAsp Thr Ile Glu Ile Thr Gly Thr Phe Lys His Arg Lys Met 565 570 575 ThrLeu Val Glu Glu Gly Phe Asn Pro Ala Val Ile Lys Asp Ala Leu 580 585 590Tyr Phe Leu Asp Asp Thr Ala Lys Met Tyr Val Pro Met Thr Glu Asp 595 600605 Ile Tyr Asn Ala Ile Ser Ala Lys Thr Leu Lys Leu 610 615 620 <210>SEQ ID NO 50 <211> LENGTH: 1173 <212> TYPE: DNA <213> ORGANISM: Homosapiens <400> SEQUENCE: 50 aagttctcgg ctggtcagtt ctgggaagat tgccagcagcacagggtgac ggtgttccag 60 tacattgggg agctgtgccg ataccttgtc aaccagcccccgagcaaggc agaacgtggc 120 cataaggtcc ggctggcagt gggcagcggg ctgcgcccagatacctggga gcgttttgtg 180 cggcgcttcg ggcccctgca ggtgctggag acatatggactgacagaggg caacgtggcc 240 accatcaact acacaggaca gcggggcgct gtggggcgtgcttcctggct ttacaagcat 300 atcttcccct tctccttgat tcgctatgat gtcaccacaggagagccaat tcgggacccc 360 caggggcact gtatggccac atctccaggt gagccagggctgctggtggc cccggtaagc 420 cagcagtccc cattcctggg ctatgctggc gggccagagctggcccaggg gaagttgcta 480 aaggatgtct tccggcctgg ggatgttttc ttcaacactggggacctgct ggtctgcgat 540 gaccaaggtt ttctccgctt ccatgatcgt actggagacaccttcaggtg gaagggggag 600 aatgtggcca caaccgaggt ggcagaggtc ttcgaggccctagattttct tcaggaggtg 660 aacgtctatg gagtcactgt gccagggcat gaaggcagggctggaatggc agccctagtt 720 ctgcgtcccc cccacgcttt ggaccttatg cagctctacacccacgtgtc tgagaacttg 780 ccaccttatg cccggccccg attcctcagg ctccaggagtctttggccac cacagagacc 840 ttcaaacagc agaaagttcg gatggcaaat gagggcttcgaccccagcac cctgtctgac 900 ccactgtacg ttctggacca ggctgtaggt gcctacctgcccctcacaac tgcccggtac 960 agcgccctcc tggcaggaaa ccttcgaatc tgagaacttccacacctgag gcacctgaga 1020 gaggaactct gtggggtggg ggccgttgca ggtgtactgggctgtcaggg atcttttcta 1080 taccagaact gcggtcacta ttttgtaata aatgtggctggagctgatcc agctgtctct 1140 gacaaaaaaa aaaaaaaaaa aaagggcggc cgc 1173<210> SEQ ID NO 51 <211> LENGTH: 330 <212> TYPE: PRT <213> ORGANISM:Homo sapiens <400> SEQUENCE: 51 Lys Phe Ser Ala Gly Gln Phe Trp Glu AspCys Gln Gln His Arg Val 1 5 10 15 Thr Val Phe Gln Tyr Ile Gly Glu LeuCys Arg Tyr Leu Val Asn Gln 20 25 30 Pro Pro Ser Lys Ala Glu Arg Gly HisLys Val Arg Leu Ala Val Gly 35 40 45 Ser Gly Leu Arg Pro Asp Thr Trp GluArg Phe Val Arg Arg Phe Gly 50 55 60 Pro Leu Gln Val Leu Glu Thr Tyr GlyLeu Thr Glu Gly Asn Val Ala 65 70 75 80 Thr Ile Asn Tyr Thr Gly Gln ArgGly Ala Val Gly Arg Ala Ser Trp 85 90 95 Leu Tyr Lys His Ile Phe Pro PheSer Leu Ile Arg Tyr Asp Val Thr 100 105 110 Thr Gly Glu Pro Ile Arg AspPro Gln Gly His Cys Met Ala Thr Ser 115 120 125 Pro Gly Glu Pro Gly LeuLeu Val Ala Pro Val Ser Gln Gln Ser Pro 130 135 140 Phe Leu Gly Tyr AlaGly Gly Pro Glu Leu Ala Gln Gly Lys Leu Leu 145 150 155 160 Lys Asp ValPhe Arg Pro Gly Asp Val Phe Phe Asn Thr Gly Asp Leu 165 170 175 Leu ValCys Asp Asp Gln Gly Phe Leu Arg Phe His Asp Arg Thr Gly 180 185 190 AspThr Phe Arg Trp Lys Gly Glu Asn Val Ala Thr Thr Glu Val Ala 195 200 205Glu Val Phe Glu Ala Leu Asp Phe Leu Gln Glu Val Asn Val Tyr Gly 210 215220 Val Thr Val Pro Gly His Glu Gly Arg Ala Gly Met Ala Ala Leu Val 225230 235 240 Leu Arg Pro Pro His Ala Leu Asp Leu Met Gln Leu Tyr Thr HisVal 245 250 255 Ser Glu Asn Leu Pro Pro Tyr Ala Arg Pro Arg Phe Leu ArgLeu Gln 260 265 270 Glu Ser Leu Ala Thr Thr Glu Thr Phe Lys Gln Gln LysVal Arg Met 275 280 285 Ala Asn Glu Gly Phe Asp Pro Ser Thr Leu Ser AspPro Leu Tyr Val 290 295 300 Leu Asp Gln Ala Val Gly Ala Tyr Leu Pro LeuThr Thr Ala Arg Tyr 305 310 315 320 Ser Ala Leu Leu Ala Gly Asn Leu ArgIle 325 330 <210> SEQ ID NO 52 <211> LENGTH: 2907 <212> TYPE: DNA <213>ORGANISM: Homo sapiens <400> SEQUENCE: 52 cgacccacgc gtccgggcgggcggggccgg gcggcgggcg gggctggcgg ggcggccggg 60 ccatgcaggg cgcagagccggctaaaccct gctgagaccc ggctccgtgc gtccaggggc 120 ggctaatgcc cctcacgctgtctacgctgc tgcaaccggg ccgcatctgg acggggcgcc 180 gcgcggcgga gccgacgccgggccacaatg ctgcttggag cctctctggt gggggtgctg 240 ctgttctcca agctggtgctgaaactgccc tggacccagg tgggattctc cctgttgttc 300 ctctacttgg gatctggcggctggcgcttc atccgggtct tcatcaagac catcaggcgc 360 gatatctttg gcggcctggtcctcctgaag gtgaaggcaa aggtgcgaca gtgcctgcag 420 gagcggcgga cagtgcccattttgtttgcc tctaccgttc ggcgccaccc cgacaagacg 480 gccctgatct tcgagggcacagatacccac tggaccttcc gccagctgga tgagtactca 540 agcagtgtag ccaacttcctgcaggcccgg ggcctggcct cgggcgatgt ggctgccatc 600 ttcatggaga accgcaatgagttcgtgggc ctatggctgg gcatggccaa gctcggtgtg 660 gaggcagccc tcatcaacaccaacctgcgg cgggatgctc tgctccactg cctcaccacc 720 tcgcgcgcac gggcccttgtctttggcagc gaaatggcct cagccatctg tgaggtccat 780 gccagcctgg acccctcgctcagcctcttc tgctctggct cctgggagcc cggtgcggtg 840 cctccaagca cagaacacctggaccctctg ctgaaagatg ctcccaagca ccttcccagt 900 tgccctgaca agggcttcacagataaactg ttctacatct acacatccgg caccacaggg 960 ctgcccaagg ccgccatcgtggtgcacagc aggtattacc gcatggctgc cctggtgtac 1020 tatggattcc gcatgcggcccaacgacatc gtctatgact gcctccccct ctaccactca 1080 gcaggaaaca tcgtgggaatcggccagtgc ctgctgcatg gcatgacggt ggtgattcgg 1140 aagaagttct cagcctcccggttctgggac gattgtatca agtacaactg cacgattgtg 1200 cagtacattg gtgaactgtgccgctacctc ctgaaccagc caccgcggga ggcagaaaac 1260 cagcaccagg ttcgcatggcactaggcaat ggcctccggc agtccatctg gaccaacttt 1320 tccagccgct tccacataccccaggtggct gagttctacg gggccacaga gtgcaactgt 1380 agcctgggca acttcgacagccaggtgggg gcctgtggtt tcaatagccg catcctgtcc 1440 ttcgtgtacc ccatccggttggtacgtgtc aacgaggaca ccatggagct gatccggggg 1500 cccgacggcg tctgcattccctgccagcca ggtgagccgg gccagctggt gggccgcatc 1560 atccagaaag accccctgcgccgcttcgat ggctacctca accagggcgc caacaacaag 1620 aagattgcca aggatgtcttcaagaagggg gaccaggcct accttactgg tgatgtgctg 1680 gtgatggacg agctgggctacctgtacttc cgagaccgca ctggggacac gttccgctgg 1740 aaaggtgaga acgtgtccaccaccgaggtg gaaggcacac tcagccgcct gctggacatg 1800 gctgacgtgg ccgtgtatggtgtcgaggtg ccaggaaccg agggccgggc cggaatggct 1860 gctgtggcca gccccactggcaactgtgac ctggagcgct ttgctcaggt cttggagaag 1920 gaactgcccc tgtatgcgcgccccatcttc ctgcgcctcc tgcctgagct gcacaaaaca 1980 ggaacctaca agttccagaagacagagcta cggaaggagg gctttgaccc ggctattgtg 2040 aaagacccgc tgttctatctagatgcccag aagggccgct acgtcccgct ggaccaagag 2100 gcctacagcc gcatccaggcaggcgaggag aagctgtgat tccccccatc cctctgaggg 2160 ccggcggatg ctggatccggagccccaggt tccgccccag agcggtcctg gacaaggcca 2220 gaccaaagca agcagggcctggcacctcca tcctgaggtg ctgcccctcc atccaaaact 2280 gccaagtgac tcattgccttcccaaccctt ccagaggctt tctgtgaaag tctcatgtcc 2340 aagttccgtc ttctgggctgggcaggccct ctggttccca ggctgagact gacgggtttt 2400 ctcaggatga tgtcttgggtgagggtaggg agaggacaag gggtcaccga gcccttccca 2460 gagagcaggg agcttataaatggaaccaga gcagaagtcc ccagactcag gaagtcaaca 2520 gagtgggcag ggacagtggtagcatccatc tggtggccaa agagaatcgt agccccagag 2580 ctgcccaagt tcactgggctccacccccac ctccaggagg ggaggagagg acctgacatc 2640 tgtaggtggc ccctgatgccccatctacag caggaggtca ggaccacgcc cctggcctct 2700 ccccactccc ccatcctcctccctgggtgg ctgcctgatt atccctcagg cagggcctct 2760 cagtccttgt gggtctgtgtcacctccatc tcagtcttgg cctggctatg aggggaggag 2820 gaatgggaga gggggctcaggggccaataa actctgcctt gagtcctcct aaaaaaaaaa 2880 aaaaaaaaaa aaaaaaaaaaaaaaaaa 2907 <210> SEQ ID NO 53 <211> LENGTH: 643 <212> TYPE: PRT <213>ORGANISM: Homo sapiens <400> SEQUENCE: 53 Met Leu Leu Gly Ala Ser LeuVal Gly Val Leu Leu Phe Ser Lys Leu 1 5 10 15 Val Leu Lys Leu Pro TrpThr Gln Val Gly Phe Ser Leu Leu Phe Leu 20 25 30 Tyr Leu Gly Ser Gly GlyTrp Arg Phe Ile Arg Val Phe Ile Lys Thr 35 40 45 Ile Arg Arg Asp Ile PheGly Gly Leu Val Leu Leu Lys Val Lys Ala 50 55 60 Lys Val Arg Gln Cys LeuGln Glu Arg Arg Thr Val Pro Ile Leu Phe 65 70 75 80 Ala Ser Thr Val ArgArg His Pro Asp Lys Thr Ala Leu Ile Phe Glu 85 90 95 Gly Thr Asp Thr HisTrp Thr Phe Arg Gln Leu Asp Glu Tyr Ser Ser 100 105 110 Ser Val Ala AsnPhe Leu Gln Ala Arg Gly Leu Ala Ser Gly Asp Val 115 120 125 Ala Ala IlePhe Met Glu Asn Arg Asn Glu Phe Val Gly Leu Trp Leu 130 135 140 Gly MetAla Lys Leu Gly Val Glu Ala Ala Leu Ile Asn Thr Asn Leu 145 150 155 160Arg Arg Asp Ala Leu Leu His Cys Leu Thr Thr Ser Arg Ala Arg Ala 165 170175 Leu Val Phe Gly Ser Glu Met Ala Ser Ala Ile Cys Glu Val His Ala 180185 190 Ser Leu Asp Pro Ser Leu Ser Leu Phe Cys Ser Gly Ser Trp Glu Pro195 200 205 Gly Ala Val Pro Pro Ser Thr Glu His Leu Asp Pro Leu Leu LysAsp 210 215 220 Ala Pro Lys His Leu Pro Ser Cys Pro Asp Lys Gly Phe ThrAsp Lys 225 230 235 240 Leu Phe Tyr Ile Tyr Thr Ser Gly Thr Thr Gly LeuPro Lys Ala Ala 245 250 255 Ile Val Val His Ser Arg Tyr Tyr Arg Met AlaAla Leu Val Tyr Tyr 260 265 270 Gly Phe Arg Met Arg Pro Asn Asp Ile ValTyr Asp Cys Leu Pro Leu 275 280 285 Tyr His Ser Ala Gly Asn Ile Val GlyIle Gly Gln Cys Leu Leu His 290 295 300 Gly Met Thr Val Val Ile Arg LysLys Phe Ser Ala Ser Arg Phe Trp 305 310 315 320 Asp Asp Cys Ile Lys TyrAsn Cys Thr Ile Val Gln Tyr Ile Gly Glu 325 330 335 Leu Cys Arg Tyr LeuLeu Asn Gln Pro Pro Arg Glu Ala Glu Asn Gln 340 345 350 His Gln Val ArgMet Ala Leu Gly Asn Gly Leu Arg Gln Ser Ile Trp 355 360 365 Thr Asn PheSer Ser Arg Phe His Ile Pro Gln Val Ala Glu Phe Tyr 370 375 380 Gly AlaThr Glu Cys Asn Cys Ser Leu Gly Asn Phe Asp Ser Gln Val 385 390 395 400Gly Ala Cys Gly Phe Asn Ser Arg Ile Leu Ser Phe Val Tyr Pro Ile 405 410415 Arg Leu Val Arg Val Asn Glu Asp Thr Met Glu Leu Ile Arg Gly Pro 420425 430 Asp Gly Val Cys Ile Pro Cys Gln Pro Gly Glu Pro Gly Gln Leu Val435 440 445 Gly Arg Ile Ile Gln Lys Asp Pro Leu Arg Arg Phe Asp Gly TyrLeu 450 455 460 Asn Gln Gly Ala Asn Asn Lys Lys Ile Ala Lys Asp Val PheLys Lys 465 470 475 480 Gly Asp Gln Ala Tyr Leu Thr Gly Asp Val Leu ValMet Asp Glu Leu 485 490 495 Gly Tyr Leu Tyr Phe Arg Asp Arg Thr Gly AspThr Phe Arg Trp Lys 500 505 510 Gly Glu Asn Val Ser Thr Thr Glu Val GluGly Thr Leu Ser Arg Leu 515 520 525 Leu Asp Met Ala Asp Val Ala Val TyrGly Val Glu Val Pro Gly Thr 530 535 540 Glu Gly Arg Ala Gly Met Ala AlaVal Ala Ser Pro Thr Gly Asn Cys 545 550 555 560 Asp Leu Glu Arg Phe AlaGln Val Leu Glu Lys Glu Leu Pro Leu Tyr 565 570 575 Ala Arg Pro Ile PheLeu Arg Leu Leu Pro Glu Leu His Lys Thr Gly 580 585 590 Thr Tyr Lys PheGln Lys Thr Glu Leu Arg Lys Glu Gly Phe Asp Pro 595 600 605 Ala Ile ValLys Asp Pro Leu Phe Tyr Leu Asp Ala Gln Lys Gly Arg 610 615 620 Tyr ValPro Leu Asp Gln Glu Ala Tyr Ser Arg Ile Gln Ala Gly Glu 625 630 635 640Glu Lys Leu <210> SEQ ID NO 54 <211> LENGTH: 1248 <212> TYPE: DNA <213>ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222>LOCATION: (1)...(1248) <223> OTHER INFORMATION: n = A,T,C or G <220>FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 262 <223> OTHERINFORMATION: n = A,T,C or G <400> SEQUENCE: 54 gtcgttggga tcctcggctgcttagatctc ggagccacct gtgttctggc ccccaagttc 60 tctacttcct gcttctgggatgactgtcgg cagcatggcg tgacagtgat cctgtatgtg 120 ggcgagctcc tgcgatacttgtgtaacatt ccccagcaac cagaggaccg gacacataca 180 gtccgcctgg caatgggcaatggactacgg gctgatgtgt ggggagacct tccagcagcg 240 tttcggtcct atttcggatctngggaagtc ttacgggctt ccacagaagg gcaacatggg 300 gctttagttc aaatattgttgggggcgctg cggggccctg ggggcaaaga tggagcttgc 360 ctcctccgaa tgctgtccccctttgagctg gtgcagttcg acatggaggc ggcggagcct 420 gtgagggaca atcagggcttctgcatccct gtagggctag gggagccggg gctgctgttg 480 accaaggtgg taagccagcaacccttcgtg ggctaccgcg gcccccgaga gctgtcggaa 540 cggaagctgg tgcgcaacgtgcggcaatcg ggcgacgttt actacaacac cggggacgta 600 ctggccatgg accgcgaaggcttcctctac ttccgcgacc gactcgggga caccttccga 660 tggaagggcg agaacgtgtccacgcacgag gtggagggcg tgttgtcgca ggtggacttc 720 ttgcaacagg ttaacgtgtatggcgtgtgc gtgccaggtt gtgagggtaa ggtgggcatg 780 gctgctgtgg cattagcccccggccagact ttcgacgggg agaagttgta ccagcacgtt 840 cgcgcttggc tccctgcctacgctaccccc catttcatcc gcatccagga cgccatggag 900 gtcaccagca cgttcaaactgatgaagacc cggttggtgc gtgagggctt caatgtgggg 960 atcgtggttg accctctgtttgtactggac aaccgggccc agtccttccg gcccctgacg 1020 cagaaatgt accaggctgtgtgtgaggga acctggaggc tctgatcacc tggccaaccc 1080 ctggggtag ggatcaaagccagccacccc caccccaaca cactcggtgt ccctttcatc 1140 tgggcctgt gtgaatcccagcctggccat accctcaacc tcagtgggct ggaaatgaca 1200 tgggccctg tagcagtggcagaataaact cagmtgygtt cacagaaa 1248 <210> SEQ ID NO 55 <211> LENGTH: 354<212> TYPE: PRT <213> ORGANISM: Homo sapiens <220> FEATURE: <221>NAME/KEY: VARIANT <222> LOCATION: (1)...(354) <223> OTHER INFORMATION:Xaa = Any Amino Acid <220> FEATURE: <221> NAME/KEY: VARIANT <222>LOCATION: 88 <223> OTHER INFORMATION: Xaa = Any Amino Acid <400>SEQUENCE: 55 Val Val Gly Ile Leu Gly Cys Leu Asp Leu Gly Ala Thr Cys ValLeu 1 5 10 15 Ala Pro Lys Phe Ser Thr Ser Cys Phe Trp Asp Asp Cys ArgGln His 20 25 30 Gly Val Thr Val Ile Leu Tyr Val Gly Glu Leu Leu Arg TyrLeu Cys 35 40 45 Asn Ile Pro Gln Gln Pro Glu Asp Arg Thr His Thr Val ArgLeu Ala 50 55 60 Met Gly Asn Gly Leu Arg Ala Asp Val Trp Gly Asp Leu ProAla Ala 65 70 75 80 Phe Arg Ser Tyr Phe Gly Ser Xaa Glu Val Leu Arg AlaSer Thr Glu 85 90 95 Gly Gln His Gly Ala Leu Val Gln Ile Leu Leu Gly AlaLeu Arg Gly 100 105 110 Pro Gly Gly Lys Asp Gly Ala Cys Leu Leu Arg MetLeu Ser Pro Phe 115 120 125 Glu Leu Val Gln Phe Asp Met Glu Ala Ala GluPro Val Arg Asp Asn 130 135 140 Gln Gly Phe Cys Ile Pro Val Gly Leu GlyGlu Pro Gly Leu Leu Leu 145 150 155 160 Thr Lys Val Val Ser Gln Gln ProPhe Val Gly Tyr Arg Gly Pro Arg 165 170 175 Glu Leu Ser Glu Arg Lys LeuVal Arg Asn Val Arg Gln Ser Gly Asp 180 185 190 Val Tyr Tyr Asn Thr GlyAsp Val Leu Ala Met Asp Arg Glu Gly Phe 195 200 205 Leu Tyr Phe Arg AspArg Leu Gly Asp Thr Phe Arg Trp Lys Gly Glu 210 215 220 Asn Val Ser ThrHis Glu Val Glu Gly Val Leu Ser Gln Val Asp Phe 225 230 235 240 Leu GlnGln Val Asn Val Tyr Gly Val Cys Val Pro Gly Cys Glu Gly 245 250 255 LysVal Gly Met Ala Ala Val Ala Leu Ala Pro Gly Gln Thr Phe Asp 260 265 270Gly Glu Lys Leu Tyr Gln His Val Arg Ala Trp Leu Pro Ala Tyr Ala 275 280285 Thr Pro His Phe Ile Arg Ile Gln Asp Ala Met Glu Val Thr Ser Thr 290295 300 Phe Lys Leu Met Lys Thr Arg Leu Val Arg Glu Gly Phe Asn Val Gly305 310 315 320 Ile Val Val Asp Pro Leu Phe Val Leu Asp Asn Arg Ala GlnSer Phe 325 330 335 Arg Pro Leu Thr Ala Glu Met Tyr Gln Ala Val Cys GluGly Thr Trp 340 345 350 Arg Leu <210> SEQ ID NO 56 <211> LENGTH: 2885<212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 56aacggcaagt aagcgcaacg caattaatgt gagtagctca ctcattaggc accccaggct 60ttacacttta tgcttccggg ctcgtatgtt gtgtggaatt gtgagcggat accaatttca 120cacaggaacc agctatgaca tgattacgaa tttaatacga ctcactatag ggaatttggc 180cctcgaggcc aagaattcgg cacgaggggt gctgagcccc tgcgcggttt ctggtgcgta 240gagactgtaa atcgctgcgc ttctcagtca tcatcatccc agcttttccc ggctcgaatt 300cagcctccaa ctcaagctcg cgggaaagac tacctgagag gagaaaagct tctgtccctg 360gaccttcttc tgagggtgga gtcggaggct ccctgctttc cagccgccca gtgacccaag 420cttaatcttc agcaccactt ggggcgacct tttcggtgca aacctacgat tctgtttctc 480aggattcctc cccatcccgc ttcgccccgg aaaagctgac aagaacttca ggtgtaagcc 540ctgagtagtg aggatctgcg gtctccgtgg agagctgtgc ctggaagaga aggacgctgg 600tgggggctga gatcagagct gtcttctggc ccagttgccc ccatgcttct gtcatggcta 660acagttctag gggctggaat ggtcgtcctg cacttcttgc agaaactcct gttcccttac 720ttttgggatg acttctggtt cgtgttgaag gtggtgctca ttataattcg gctgaagaag 780tatgaaaaga gaggggagct ggtgactgtg ctggataaat tcttgagtca tgccaaaaga 840caacctcgga aacctttcat catctatgag ggagacatct acacctatca ggatgtagac 900aaaaggagca gcagagtggc ccatgtcttc ctgaaccatt cctctctgaa aaagggggac 960cggtggctc tgctgatgag caatgagccg gacttcgttc acgtgtggtt cggcctcgcc 1020agctgggct gcgtggtggc ctttctcaac accaacattc gctccaactc cctcctgaat 1080gcatccgcg cctgtgggcc cagagcccta gtggtgggcg cagatttgct tggaacggta 1140aagaaatcc ttccaagcct ctcagaaaat atcagtgttt gggggatgaa agattctgtt 1200cacaaggtg taatttcact caaagaaaaa ctgagcacct cacctgatga gcccgtgcca 1260gcagccacc atgttgtctc actcctcaag tctacttgtc tttacatttt tacctctgga 1320caacaggtc taccaaaagc agctgtgatt agtcagctgc aggttttaag gggttctgct 1380tcctgtggg cttttggttg tactgctcat gacattgttt atataaccct tcctctgtat 1440atagttcag cagctatcct gggaatttct ggatgtgttg agttgggtgc cacttgtgtg 1500taaagaaga aattttcagc aagccagttt tggagtgact gcaagaagta tgatgtgact 1560tgtttcagt atattggaga actttgtcgc tacctttgca aacaatctaa gagagaagga 1620aaaaggatc ataaggtgcg tttggcaatt ggaaatggca tacggagtga tgtatggaga 1680aatttttag acagatttgg aaatataaag gtgtgtgaac tttatgcagc taccgaatca 1740gcatatctt tcatgaacta cactgggaga attggagcaa ttgggagaac aaatttgttt 1800acaaacttc tttccacttt tgacttaata aagtatgact ttcagaaaga tgaacccatg 1860gaaatgagc agggttggtg tattcatgtg aaaaaaggag aacctggact tctcatttct 1920gagtgaatg caaaaaatcc cttctttggc tatgctgggc cttataagca cacaaaagac 1980aattgcttt gtgatgtttt taagaaggga gatgtttacc ttaatactgg agacttaata 2040tccaggatc aggacaattt cctttatttt tgggaccgta ctggagacac tttcagatgg 2100aaggagaaa atgtcgcaac cactgaggtt gctgatgtta ttggaatgtt ggatttcata 2160aggaagcaa acgtctatgg tgtggctata tcaggttatg aaggaagagc aggaatggct 2220ctattattt taaaaccaaa tacatcttta gatttggaaa aagtttatga acaagttgta 2280catttctac cagcttatgc ttgtccacga tttttaagaa ttcaggaaaa aatggaagca 2340caggaacat tcaaactatt gaagcatcag ttggtggaag atggatttaa tccactgaaa 2400tttctgaac cactttactt catggataac ttgaaaaagt cttatgttct actgaccagg 2460aactttatg atcaaataat gttaggggaa ataaaacttt aagattttta tatctagaac 2520ttcatatgc tttcttagga agagtgagag gggggtatat gattctttat gaaatgggga 2580agggagcta acattaatta tgcatgtact atatttcctt aatatgagag ataatttttt 2640attgcataa gaattttaat ttcttttaat tgatataaac attagttgat tattcttttt 2700tctatttgg agattcagtg cataactaag tattttcctt aatactaaag attttaaata 2760taaatagtg gctagcggtt tggacaatca ctaaaaatgt actttctaat aagtaaaatt 2820ctaattttg aataaaagat taaattttac tgaaaaaaaa aaaaaaaaaa aaaattggcg 2880ccgc 2885 <210> SEQ ID NO 57 <211> LENGTH: 619 <212> TYPE: PRT <213>ORGANISM: Homo sapiens <400> SEQUENCE: 57 Met Leu Leu Ser Trp Leu ThrVal Leu Gly Ala Gly Met Val Val Leu 1 5 10 15 His Phe Leu Gln Lys LeuLeu Phe Pro Tyr Phe Trp Asp Asp Phe Trp 20 25 30 Phe Val Leu Lys Val ValLeu Ile Ile Ile Arg Leu Lys Lys Tyr Glu 35 40 45 Lys Arg Gly Glu Leu ValThr Val Leu Asp Lys Phe Leu Ser His Ala 50 55 60 Lys Arg Gln Pro Arg LysPro Phe Ile Ile Tyr Glu Gly Asp Ile Tyr 65 70 75 80 Thr Tyr Gln Asp ValAsp Lys Arg Ser Ser Arg Val Ala His Val Phe 85 90 95 Leu Asn His Ser SerLeu Lys Lys Gly Asp Thr Val Ala Leu Leu Met 100 105 110 Ser Asn Glu ProAsp Phe Val His Val Trp Phe Gly Leu Ala Lys Leu 115 120 125 Gly Cys ValVal Ala Phe Leu Asn Thr Asn Ile Arg Ser Asn Ser Leu 130 135 140 Leu AsnCys Ile Arg Ala Cys Gly Pro Arg Ala Leu Val Val Gly Ala 145 150 155 160Asp Leu Leu Gly Thr Val Glu Glu Ile Leu Pro Ser Leu Ser Glu Asn 165 170175 Ile Ser Val Trp Gly Met Lys Asp Ser Val Pro Gln Gly Val Ile Ser 180185 190 Leu Lys Glu Lys Leu Ser Thr Ser Pro Asp Glu Pro Val Pro Arg Ser195 200 205 His His Val Val Ser Leu Leu Lys Ser Thr Cys Leu Tyr Ile PheThr 210 215 220 Ser Gly Thr Thr Gly Leu Pro Lys Ala Ala Val Ile Ser GlnLeu Gln 225 230 235 240 Val Leu Arg Gly Ser Ala Val Leu Trp Ala Phe GlyCys Thr Ala His 245 250 255 Asp Ile Val Tyr Ile Thr Leu Pro Leu Tyr HisSer Ser Ala Ala Ile 260 265 270 Leu Gly Ile Ser Gly Cys Val Glu Leu GlyAla Thr Cys Val Leu Lys 275 280 285 Lys Lys Phe Ser Ala Ser Gln Phe TrpSer Asp Cys Lys Lys Tyr Asp 290 295 300 Val Thr Val Phe Gln Tyr Ile GlyGlu Leu Cys Arg Tyr Leu Cys Lys 305 310 315 320 Gln Ser Lys Arg Glu GlyGlu Lys Asp His Lys Val Arg Leu Ala Ile 325 330 335 Gly Asn Gly Ile ArgSer Asp Val Trp Arg Glu Phe Leu Asp Arg Phe 340 345 350 Gly Asn Ile LysVal Cys Glu Leu Tyr Ala Ala Thr Glu Ser Ser Ile 355 360 365 Ser Phe MetAsn Tyr Thr Gly Arg Ile Gly Ala Ile Gly Arg Thr Asn 370 375 380 Leu PheTyr Lys Leu Leu Ser Thr Phe Asp Leu Ile Lys Tyr Asp Phe 385 390 395 400Gln Lys Asp Glu Pro Met Arg Asn Glu Gln Gly Trp Cys Ile His Val 405 410415 Lys Lys Gly Glu Pro Gly Leu Leu Ile Ser Arg Val Asn Ala Lys Asn 420425 430 Pro Phe Phe Gly Tyr Ala Gly Pro Tyr Lys His Thr Lys Asp Lys Leu435 440 445 Leu Cys Asp Val Phe Lys Lys Gly Asp Val Tyr Leu Asn Thr GlyAsp 450 455 460 Leu Ile Val Gln Asp Gln Asp Asn Phe Leu Tyr Phe Trp AspArg Thr 465 470 475 480 Gly Asp Thr Phe Arg Trp Lys Gly Glu Asn Val AlaThr Thr Glu Val 485 490 495 Ala Asp Val Ile Gly Met Leu Asp Phe Ile GlnGlu Ala Asn Val Tyr 500 505 510 Gly Val Ala Ile Ser Gly Tyr Glu Gly ArgAla Gly Met Ala Ser Ile 515 520 525 Ile Leu Lys Pro Asn Thr Ser Leu AspLeu Glu Lys Val Tyr Glu Gln 530 535 540 Val Val Thr Phe Leu Pro Ala TyrAla Cys Pro Arg Phe Leu Arg Ile 545 550 555 560 Gln Glu Lys Met Glu AlaThr Gly Thr Phe Lys Leu Leu Lys His Gln 565 570 575 Leu Val Glu Asp GlyPhe Asn Pro Leu Lys Ile Ser Glu Pro Leu Tyr 580 585 590 Phe Met Asp AsnLeu Lys Lys Ser Tyr Val Leu Leu Thr Arg Glu Leu 595 600 605 Tyr Asp GlnIle Met Leu Gly Glu Ile Lys Leu 610 615 <210> SEQ ID NO 58 <211> LENGTH:3098 <212> TYPE: DNA <213> ORGANISM: Rattus norvegicus <400> SEQUENCE:58 aagttcccac tccagacttc tgcgagaacc cgtgaggaag cagcgagaac cgggggtttg 60caagccagag aaggatgcgg actccgggag caggaacagc ctctgtggcc tcattggggc 120tgctttggct tctgggactt ccgtggacct ggagcgcggc ggcggcgttc ggtgtgtacg 180tgggtagcgg tggctggcga tttctgcgta tcgtctgcaa gacggcgagg cgagacctct 240ttggcctctc tgttctgatc cgcgtgcggc tagagctacg acgacaccgg cgagcaggag 300acacgatccc acgcatcttc caggccgtgg cccagcgaca gccggagcgc ctggcgctgg 360tagatgcgag tagcggtatc tgctggacct tcgcacagct agacacctac tccaatgctg 420tggccaatct gttcctccag ctgggctttg cgccaggcga tgtggtggct gtgttcctgg 480aaggccggcc cgagttcgtg ggactgtggc tgggcctggc caaggccggt gtagtggctg 540cgcttctcaa tgtcaacctg aggcgggagc cccttgcctt ctgcttgggc acatcagctg 600ccaaggccct catttatggc ggggagatgg cagcggcggt ggcggaggtg agtgagcagc 660tggggaagag cctgctcaag ttctgctctg gagatctggg gcctgagagc gtcctgcctg 720acacgcagct tctggacccc atgcttgctg aggcgcccac cacacccctg gcacaggccc 780caggcaaggg catggatgat cggctatttt acatctatac ttctgggacc accggacttc 840ctaaggcggc cattgtggtg cacagcaggt actaccgcat cgcagccttc ggccaccatt 900cctacagcat gcgggccaac gatgtgctct atgactgcct acctctctac cactcagcag 960ggaacatcat gggcgtggga cagtgtatca tctacgggtt aacggtggta ctgcgcaaga 1020agttctccgc cagccgcttc tgggacgact gtgtcaaata taattgcacg gtagtgcagt 1080acatcggtga aatatgccgc tacctgctaa ggcagccggt tcgcgatgta gagcggcggc 1140accgcgtgcg cctggccgtg ggtaacggac tgcggccagc catctgggag gagttcacgc 1200agggtttcgg tgtgcgacag attggcgagt tctacggcgc caccgaatgc aactgcagca 1260ttgccaacat ggacggcaag gtcggctcct gcggcttcaa cagccgtatc ctcacgcatg 1320tgtaccccat ccgtctggtc aaggtcaacg aggacacgat ggagccactg agggactccc 1380aaggcctctg catcccgtgc cagcccgggg aacctgggct tctcgtgggc cagatcaacc 1440agcaagaccc tctgcggcgc ttcgatggct atgttagtga cagcgccacc aacaagaaga 1500ttgcccacag cgtgttccga aagggggaca gcgcctacct ttcaggtgac gtgctagtga 1560tggacgagct ggggtacatg tacttccgtg accgcagcgg ggataccttc cgatggcgcg 1620gcgagaacgt atccaccacg gaggtggaag ccgtgctgag ccgcctgttg ggccagacgg 1680acgtggctgt gtatggagtg gctgtgccag gagtggaggg gaaaagcggc atggcggcca 1740ttgcagaccc ccacaaccag ctggacccta actcaatgta ccaggaattg cagaaggttc 1800ttgcatccta tgcccagccc atcttcctgc gtcttctgcc ccaagtggat acaacaggca 1860ccttcaagat ccagaagacc cgactacagc gtgaaggctt tgacccccgc cagacctcag 1920accggctctt ctttctagac ctgaaacagg gacgctacct acccctggat gagagagtcc 1980atgcccgcat ctgcgcaggc gacttctcac tctgagcctg gtgagtggga tggccctgga 2040cttgtgagac cagggagccg gacacccctg ttcaggtgtt tctcctgcct ggccacgtgg 2100ccagcagcac ctgtgggtgc aggaaactgg aacctgagtg gccgggtgtc cctttcctac 2160aacccaccat gcacacatct agcctctgcc ttggtctttt tctccatctc tttcctccgt 2220gcccagcagg agccccacag acacattggc tgctgtgtcc tgcagtggga ccggtgtcta 2280ggggtccatg ctgcaggctg tgacccgcac tggtgcccac ctcccttccc cattgtgcct 2340taggttcctc cactgtgcgc cggtgaagca agtggggacc cacatagctg ttgtccctgc 2400tgagggttgg tagcaaatgc accctcatgt cagctgggag acacatgcag tctcccactg 2460acccccaatc aactgaagat actgttttgt attattgttt tgagataggg tctcactgtg 2520gaggccaagc tggcctcagg ctcaccactc tactgcctcc gggcaccagc ctgcagtttg 2580atgacatgta tgcactattg ttctaagggt cttctgagtc cctgctttcc cctcatgtcc 2640taaaaccttc cagaactgac tctgatcact tggatgtagc tagtgttggc cctgcccacg 2700tgtgtcaatt caggggtccc caggcatcat ctctggaggc cctaaccttg gcaaagcttg 2760gatgtcctca catcacagca ggagacccag gaaggttgct gtggtgtctc ttgggcaccc 2820ctggcggcag ccgtggacat gcttccctgc tgtgatagcc caaactgttg cctatgacat 2880ttgaggtcta cccttctggc tgccatggtc cccattgaga tctttggtga ctcacctcag 2940ccaccaagcc aggcctctgc cttccttcag ctctaagggc atgaagggtg tggacagagc 3000agccacaggc tgcccacagt cacccacatg caagtgttat ttccttgttt gttttaaaaa 3060aataaacatg ctgagccttg aaaaaaaaaa aaaaaaaa 3098 <210> SEQ ID NO 59 <211>LENGTH: 630 <212> TYPE: PRT <213> ORGANISM: Rattus norvegicus <400>SEQUENCE: 59 Met Arg Thr Pro Gly Ala Gly Thr Ala Ser Val Ala Ser Leu GlyLeu 1 5 10 15 Leu Trp Leu Leu Gly Leu Pro Trp Thr Trp Ser Ala Ala AlaAla Phe 20 25 30 Gly Val Tyr Val Gly Ser Gly Gly Trp Arg Phe Leu Arg IleVal Cys 35 40 45 Lys Thr Ala Arg Arg Asp Leu Phe Gly Leu Ser Val Leu IleArg Val 50 55 60 Arg Leu Glu Leu Arg Arg His Arg Arg Ala Gly Asp Thr IlePro Arg 65 70 75 80 Ile Phe Gln Ala Val Ala Gln Arg Gln Pro Glu Arg LeuAla Leu Val 85 90 95 Asp Ala Ser Ser Gly Ile Cys Trp Thr Phe Ala Gln LeuAsp Thr Tyr 100 105 110 Ser Asn Ala Val Ala Asn Leu Phe Leu Gln Leu GlyPhe Ala Pro Gly 115 120 125 Asp Val Val Ala Val Phe Leu Glu Gly Arg ProGlu Phe Val Gly Leu 130 135 140 Trp Leu Gly Leu Ala Lys Ala Gly Val ValAla Ala Leu Leu Asn Val 145 150 155 160 Asn Leu Arg Arg Glu Pro Leu AlaPhe Cys Leu Gly Thr Ser Ala Ala 165 170 175 Lys Ala Leu Ile Tyr Gly GlyGlu Met Ala Ala Ala Val Ala Glu Val 180 185 190 Ser Glu Gln Leu Gly LysSer Leu Leu Lys Phe Cys Ser Gly Asp Leu 195 200 205 Gly Pro Glu Ser ValLeu Pro Asp Thr Gln Leu Leu Asp Pro Met Leu 210 215 220 Ala Glu Ala ProThr Thr Pro Leu Ala Gln Ala Pro Gly Lys Gly Met 225 230 235 240 Asp AspArg Leu Phe Tyr Ile Tyr Thr Ser Gly Thr Thr Gly Leu Pro 245 250 255 LysAla Ala Ile Val Val His Ser Arg Tyr Tyr Arg Ile Ala Ala Phe 260 265 270Gly His His Ser Tyr Ser Met Arg Ala Asn Asp Val Leu Tyr Asp Cys 275 280285 Leu Pro Leu Tyr His Ser Ala Gly Asn Ile Met Gly Val Gly Gln Cys 290295 300 Ile Ile Tyr Gly Leu Thr Val Val Leu Arg Lys Lys Phe Ser Ala Ser305 310 315 320 Arg Phe Trp Asp Asp Cys Val Lys Tyr Asn Cys Thr Val ValGln Tyr 325 330 335 Ile Gly Glu Ile Cys Arg Tyr Leu Leu Arg Gln Pro ValArg Asp Val 340 345 350 Glu Arg Arg His Arg Val Arg Leu Ala Val Gly AsnGly Leu Arg Pro 355 360 365 Ala Ile Trp Glu Glu Phe Thr Gln Gly Phe GlyVal Arg Gln Ile Gly 370 375 380 Glu Phe Tyr Gly Ala Thr Glu Cys Asn CysSer Ile Ala Asn Met Asp 385 390 395 400 Gly Lys Val Gly Ser Cys Gly PheAsn Ser Arg Ile Leu Thr His Val 405 410 415 Tyr Pro Ile Arg Leu Val LysVal Asn Glu Asp Thr Met Glu Pro Leu 420 425 430 Arg Asp Ser Gln Gly LeuCys Ile Pro Cys Gln Pro Gly Glu Pro Gly 435 440 445 Leu Leu Val Gly GlnIle Asn Gln Gln Asp Pro Leu Arg Arg Phe Asp 450 455 460 Gly Tyr Val SerAsp Ser Ala Thr Asn Lys Lys Ile Ala His Ser Val 465 470 475 480 Asp GluLeu Gly Tyr Met Tyr Phe Arg Asp Arg Ser Gly Asp Thr Phe 485 490 495 ArgTrp Arg Gly Glu Asn Val Ser Thr Thr Glu Val Glu Ala Val Leu 500 505 510Ser Arg Leu Leu Gly Gln Thr Asp Val Ala Val Tyr Gly Val Ala Val 515 520525 Pro Gly Val Glu Gly Lys Ser Gly Met Ala Ala Ile Ala Asp Pro His 530535 540 Asn Gln Leu Asp Pro Asn Ser Met Tyr Gln Glu Leu Gln Lys Val Leu545 550 555 560 Ala Ser Tyr Ala Gln Pro Ile Phe Leu Arg Leu Leu Pro GlnVal Asp 565 570 575 Thr Thr Gly Thr Phe Lys Ile Gln Lys Thr Arg Leu GlnArg Glu Gly 580 585 590 Phe Asp Pro Arg Gln Thr Ser Asp Arg Leu Phe PheLeu Asp Leu Lys 595 600 605 Gln Gly Arg Tyr Leu Pro Leu Asp Glu Arg ValHis Ala Arg Ile Cys 610 615 620 Ala Gly Asp Phe Ser Leu 625 630 <210>SEQ ID NO 60 <211> LENGTH: 2963 <212> TYPE: DNA <213> ORGANISM: Rattusnorvegicus <400> SEQUENCE: 60 gacacagtac tgccgatgtt ggacagaggatcgcttaaca gaacgaaatc tcaaaacaaa 60 ttaacaggac ccggttgctt gatttcccaaatcagaaaag gctcgaaatg tctagagggg 120 ctgactgatg cagcggtgac ccggactggagacagttgga cgcgatcatc tctggtgctt 180 ttgttcaacc ttgaaacctt cgccacaggagacttgcctg agcagagaag caaacgtgga 240 gaaacaaaga gagatctagc gaaaagcctctgggaccaag gaggggaggt gggactctgg 300 gttggcggtg gcacctgctg ccggctattaataatagggt cgcgatgcgt ttataaggtg 360 tttgattaaa caaagactct atgagagaagaataactagc aacagcccca cgtctgagtc 420 gtcgcctccg acctttttca acgtgggttctttgggccga gcgtcgtttg ccgagaacta 480 gatctcacct gaccccagac gctgaaaacaagcgctgtgg catcctgggc cacccaagct 540 gacaagggcg cgccccctga gcacacgaggtgccccacga gggggaggga cccacagccg 600 tcccgcccgc accgcggtgt ccgctgcgggcacctgcagc cgagccgcca cccgcagtcg 660 cagcgcgtcc ggcggccgaa cccggtcgtcagctcgtcag cacctgctct gcttctctcc 720 cgcccgccgc cgcgctgcac gcctcgagcgctccctcggc cccggcgggg accggggacc 780 ccgcagccac cgccatgctg cctgtgctctacaccggcct ggcggggctg ctgctgctgc 840 ctctgctgct cacctgctgc tgcccctacctcctccagga cgtgcggttc ttcctgcaac 900 tggccaacat ggcccggcag gtgcgcagctaccggcagcg gcgacccgtg cgcaccatcc 960 tgcatgtctt cttggagcaa gcgcgcaagaccccgcacaa gcccttcctg ctgtttcgcg 1020 acgagacgct tacctacgcc caggtagaccggcgcagcaa ccaagtagcg cgagcgctgc 1080 atgatcacct gggcctgcgg cagggggattgcgtggccct cttcatgggc aatgagccgg 1140 cctacgtgtg gctctggctg ggactgctcaaactgggctg tcccatggcg tgcctcaact 1200 acaacatccg tgccaagtct ctgctacactgctttcagtg ctgcggggcg aaggtgctgc 1260 tggcctcccc agagctacac gaagctgtcgaggaggttct tccaaccctg aaaaaggagg 1320 gcgtgtccgt cttctacgta agcagaacttctaacactaa tggcgtggac acagtactgg 1380 acaaagtaga cggggtgtcg gcggaccccatcccggagtc gtggaggtct gaagtcacgt 1440 tcaccacacc cgcagtctac atatatacttcgggcaccac aggtcttcca aaggctgcaa 1500 ccattaatca ccatcgcctc tggtatgggaccagccttgc cctgaggtcc ggaattaagg 1560 ctcatgacgt catctacacc accatgcccctgtaccacag cgcggcgctc atgattggcc 1620 tccacggatg cattgtggtt ggggctacatttgctttgcg gagcaaattt tcagccagcc 1680 agttttggga cgactgcagg aaatacaacgccactgtcat tcagtacatc ggtgaactgc 1740 ttcggtacct ctgcaacacg ccccagaaaccaaatgaccg ggaccacaaa gtgaaaatag 1800 cactaggaaa tggcttacga ggagatgtgtggagagagtt catcaagaga tttggggaca 1860 ttcacattta tgagttctac gcttccactgaaggcaacat tggatttatg aactatccaa 1920 gaaaaatcgg agctgttgga agagaaaattacctacaaaa aaaagttgta aggcacgagc 1980 tgatcaagta tgacgtggag aaggatgagcctgtccgtga tgcaaatgga tattgcatca 2040 aagtccccaa aggagaggtt ggactcttgatttgcaaaat cacagagctc acaccatttt 2100 ttggctatgc tggaggaaag acccagacagagaagaaaaa gctcagagat gtttttaaga 2160 aaggagacgt ctacttcaac agtggcgatctcctgatgat cgaccgtgaa aatttcatct 2220 attttcacga cagagttgga gacaccttccggtggaaagg agagaatgta gctaccacgg 2280 aagtcgctga cattgtggga ctggtagattttgttgaaga agtgaatgtt tacggtgtgc 2340 ccgtgccagg tcatgaaggt cgcatcgggatggcctcgat caagatgaaa gaaaactacg 2400 agttcaatgg aaagaaactc tttcagcacatctcggagta cctgcccagt tactcgaggc 2460 ctcggttcct gagaatacaa gataccattgagatcaccgg gacttttaaa caccgcaaag 2520 tgaccctgat ggaagagggc tttaacccctcagtcatcaa agataccttg tatttcatgg 2580 atgacacaga aaaaacatac gtgcccatgactgaggacat ttataatgcc ataattgata 2640 agactctgaa gctctgaatg ttgcctggctcctaacactt ccagaaagaa acacaatagg 2700 cctagcatag ccccttcaca tgtgtaatccaactttaact tgattaaagg ttataggtgt 2760 gatttttcct aggaaattat tcatttaaaggacaattgtt tgtttgtttg tttgtttttt 2820 attaattaca ccagaacgtt tgcaagtaaaaagatttaaa gtcacttatt tttcaatgtg 2880 cacctgccat ttgtccttgc aaacttagcttcttggagag agggccttat ttttttaaag 2940 acataataaa ctatgtaaac act 2963<210> SEQ ID NO 61 <211> LENGTH: 620 <212> TYPE: PRT <213> ORGANISM:Rattus norvegicus <400> SEQUENCE: 61 Met Leu Pro Val Leu Tyr Thr Gly LeuAla Gly Leu Leu Leu Leu Pro 1 5 10 15 Leu Leu Leu Thr Cys Cys Cys ProTyr Leu Leu Gln Asp Val Arg Phe 20 25 30 Phe Leu Gln Leu Ala Asn Met AlaArg Gln Val Arg Ser Tyr Arg Gln 35 40 45 Arg Arg Pro Val Arg Thr Ile LeuHis Val Phe Leu Glu Gln Ala Arg 50 55 60 Lys Thr Pro His Lys Pro Phe LeuLeu Phe Arg Asp Glu Thr Leu Thr 65 70 75 80 Tyr Ala Gln Val Asp Arg ArgSer Asn Gln Val Ala Arg Ala Leu His 85 90 95 Asp His Leu Gly Leu Arg GlnGly Asp Cys Val Ala Leu Phe Met Gly 100 105 110 Asn Glu Pro Ala Tyr ValTrp Leu Trp Leu Gly Leu Leu Lys Leu Gly 115 120 125 Cys Pro Met Ala CysLeu Asn Tyr Asn Ile Arg Ala Lys Ser Leu Leu 130 135 140 His Cys Phe GlnCys Cys Gly Ala Lys Val Leu Leu Ala Ser Pro Glu 145 150 155 160 Leu HisGlu Ala Val Glu Glu Val Leu Pro Thr Leu Lys Lys Glu Gly 165 170 175 ValSer Val Phe Tyr Val Ser Arg Thr Ser Asn Thr Asn Gly Val Asp 180 185 190Thr Val Leu Asp Lys Val Asp Gly Val Ser Ala Asp Pro Ile Pro Glu 195 200205 Ser Trp Arg Ser Glu Val Thr Phe Thr Thr Pro Ala Val Tyr Ile Tyr 210215 220 Thr Ser Gly Thr Thr Gly Leu Pro Lys Ala Ala Thr Ile Asn His His225 230 235 240 Arg Leu Trp Tyr Gly Thr Ser Leu Ala Leu Arg Ser Gly IleLys Ala 245 250 255 His Asp Val Ile Tyr Thr Thr Met Pro Leu Tyr His SerAla Ala Leu 260 265 270 Met Ile Gly Leu His Gly Cys Ile Val Val Gly AlaThr Phe Ala Leu 275 280 285 Arg Ser Lys Phe Ser Ala Ser Gln Phe Trp AspAsp Cys Arg Lys Tyr 290 295 300 Asn Ala Thr Val Ile Gln Tyr Ile Gly GluLeu Leu Arg Tyr Leu Cys 305 310 315 320 Asn Thr Pro Gln Lys Pro Asn AspArg Asp His Lys Val Lys Ile Ala 325 330 335 Leu Gly Asn Gly Leu Arg GlyAsp Val Trp Arg Glu Phe Ile Lys Arg 340 345 350 Phe Gly Asp Ile His IleTyr Glu Phe Tyr Ala Ser Thr Glu Gly Asn 355 360 365 Ile Gly Phe Met AsnTyr Pro Arg Lys Ile Gly Ala Val Gly Arg Glu 370 375 380 Asn Tyr Leu GlnLys Lys Val Val Arg His Glu Leu Ile Lys Tyr Asp 385 390 395 400 Val GluLys Asp Glu Pro Val Arg Asp Ala Asn Gly Tyr Cys Ile Lys 405 410 415 ValPro Lys Gly Glu Val Gly Leu Leu Ile Cys Lys Ile Thr Glu Leu 420 425 430Thr Pro Phe Phe Gly Tyr Ala Gly Gly Lys Thr Gln Thr Glu Lys Lys 435 440445 Lys Leu Arg Asp Val Phe Lys Lys Gly Asp Val Tyr Phe Asn Ser Gly 450455 460 Asp Leu Leu Met Ile Asp Arg Glu Asn Phe Ile Tyr Phe His Asp Arg465 470 475 480 Val Gly Asp Thr Phe Arg Trp Lys Gly Glu Asn Val Ala ThrThr Glu 485 490 495 Val Ala Asp Ile Val Gly Leu Val Asp Phe Val Glu GluVal Asn Val 500 505 510 Tyr Gly Val Pro Val Pro Gly His Glu Gly Arg IleGly Met Ala Ser 515 520 525 Ile Lys Met Lys Glu Asn Tyr Glu Phe Asn GlyLys Lys Leu Phe Gln 530 535 540 His Ile Ser Glu Tyr Leu Pro Ser Tyr SerArg Pro Arg Phe Leu Arg 545 550 555 560 Ile Gln Asp Thr Ile Glu Ile ThrGly Thr Phe Lys His Arg Lys Val 565 570 575 Thr Leu Met Glu Glu Gly PheAsn Pro Ser Val Ile Lys Asp Thr Leu 580 585 590 Tyr Phe Met Asp Asp ThrGlu Lys Thr Tyr Val Pro Met Thr Glu Asp 595 600 605 Ile Tyr Asn Ala IleIle Asp Lys Thr Leu Lys Leu 610 615 620 <210> SEQ ID NO 62 <211> LENGTH:1350 <212> TYPE: DNA <213> ORGANISM: Rattus norvegicus <400> SEQUENCE:62 gatcagctct tctatatcta cacgtcgggc accacggggc tacccaaagc tgccattgtg 60gtgcacagca ggtattaccg aatggctgcc ctggtgtact atggattccg catgcggcct 120gatgacattg tctatgactg cctccccctc taccactcag caggaaacat tgtggggatt 180ggccagtgcg tactccacgg catgactgtg gtgatccgga agaagttttc agcctcccgg 240ttctgggatg actgtatcaa gtacaactgc acaattgtac agtacattgg tgagctttgc 300cgctacctcc tgaaccagcc accccgtgag gctgagtctc ggcacaaggt gcgcatggca 360ctgggcaacg gtctccggca gtccatctgg accgacttct ccagccgttt ccacattccc 420aaggtggccg agttctacgg ggccaccgag tgcaactgta gcttgggcaa ctttgacagc 480caggtggggg cctgtggctt caatagccgc atcctgtcct ttgtgtaccc catccgcttg 540gtacgagtca atgaggatac catggaactg atccggggac ccgatggcgt ctgcattccc 600tgtcaaccag gccagccagg ccagctggtg ggtcgcatca tccagcagga ccccctacgc 660cgttttgatg gctacctcaa ccagggtgcc aacaacaaga agattgctag tgatgtcttc 720aagaaagggg accaagccta cctcactggt gacgtgctgg tgatggatga gctgggctac 780ctgtacttcc gagaccgcac aggggacacg ttccgctgga aaggggagaa tgtgtctacc 840actgaagtgg agggcacact cagccgcctg cttcagatgg cagatgtggc tgtttatggt 900gttgaggtgc caggagctga gggccgagca ggaatggctg ctgtggcaag ccccactagc 960aactgtgacc tggagagctt tgcacagacc ttgaaaaagg agctgcccct gtacgcccgc 1020cccatcttcc tccgcttctt gcctgagctg cacaaaacag gaaccttcaa gttccagaag 1080acagagttgc ggaaggaggg ctttgacccg tctgttgtga aagacccact cttctatttg 1140gatgcccgga caggctgcta tgttgcactg gaccaagagg cctatacccg catccaggca 1200ggcgaggaga agctgtgatt tcccccacat ccctctgagg gccagaggat gctggattca 1260gagccccagc ttccactcca gaaggggtct gggcaaggcc agaccaaagc tagcagggcc 1320cgcaccttca ccctaggtgc tgatccccct 1350 <210> SEQ ID NO 63 <211> LENGTH:405 <212> TYPE: PRT <213> ORGANISM: Rattus norvegicus <400> SEQUENCE: 63Asp Gln Leu Phe Tyr Ile Tyr Thr Ser Gly Thr Thr Gly Leu Pro Lys 1 5 1015 Ala Ala Ile Val Val His Ser Arg Tyr Tyr Arg Met Ala Ala Leu Val 20 2530 Tyr Tyr Gly Phe Arg Met Arg Pro Asp Asp Ile Val Tyr Asp Cys Leu 35 4045 Pro Leu Tyr His Ser Ala Gly Asn Ile Val Gly Ile Gly Gln Cys Val 50 5560 Leu His Gly Met Thr Val Val Ile Arg Lys Lys Phe Ser Ala Ser Arg 65 7075 80 Phe Trp Asp Asp Cys Ile Lys Tyr Asn Cys Thr Ile Val Gln Tyr Ile 8590 95 Gly Glu Leu Cys Arg Tyr Leu Leu Asn Gln Pro Pro Arg Glu Ala Glu100 105 110 Ser Arg His Lys Val Arg Met Ala Leu Gly Asn Gly Leu Arg GlnSer 115 120 125 Ile Trp Thr Asp Phe Ser Ser Arg Phe His Ile Pro Lys ValAla Glu 130 135 140 Phe Tyr Gly Ala Thr Glu Cys Asn Cys Ser Leu Gly AsnPhe Asp Ser 145 150 155 160 Gln Val Gly Ala Cys Gly Phe Asn Ser Arg IleLeu Ser Phe Val Tyr 165 170 175 Pro Ile Arg Leu Val Arg Val Asn Glu AspThr Met Glu Leu Ile Arg 180 185 190 Gly Pro Asp Gly Val Cys Ile Pro CysGln Pro Gly Gln Pro Gly Gln 195 200 205 Leu Val Gly Arg Ile Ile Gln GlnAsp Pro Leu Arg Arg Phe Asp Gly 210 215 220 Tyr Leu Asn Gln Gly Ala AsnAsn Lys Lys Ile Ala Ser Asp Val Phe 225 230 235 240 Lys Lys Gly Asp GlnAla Tyr Leu Thr Gly Asp Val Leu Val Met Asp 245 250 255 Glu Leu Gly TyrLeu Tyr Phe Arg Asp Arg Thr Gly Asp Thr Phe Arg 260 265 270 Trp Lys GlyGlu Asn Val Ser Thr Thr Glu Val Glu Gly Thr Leu Ser 275 280 285 Arg LeuLeu Gln Met Ala Asp Val Ala Val Tyr Gly Val Glu Val Pro 290 295 300 GlyAla Glu Gly Arg Ala Gly Met Ala Ala Val Ala Ser Pro Thr Ser 305 310 315320 Asn Cys Asp Leu Glu Ser Phe Ala Gln Thr Leu Lys Lys Glu Leu Pro 325330 335 Leu Tyr Ala Arg Pro Ile Phe Leu Arg Phe Leu Pro Glu Leu His Lys340 345 350 Thr Gly Thr Phe Lys Phe Gln Lys Thr Glu Leu Arg Lys Glu GlyPhe 355 360 365 Asp Pro Ser Val Val Lys Asp Pro Leu Phe Tyr Leu Asp AlaArg Thr 370 375 380 Gly Cys Tyr Val Ala Leu Asp Gln Glu Ala Tyr Thr ArgIle Gln Ala 385 390 395 400 Gly Glu Glu Lys Leu 405 <210> SEQ ID NO 64<211> LENGTH: 3217 <212> TYPE: DNA <213> ORGANISM: Mus musculus <400>SEQUENCE: 64 atgcgggctc ctggagcagg aacagcctct gtggcctcac tggcgctgctttggtttctg 60 ggacttccgt ggacctggag cgcggcggcg gcgttctgtg tgtacgtgggtggcggcggc 120 tggcgctttc tgcgtatcgt ctgcaagacg gcgaggcgag acctctttggcctctctgtt 180 ctgattcgtg ttcggctaga gctgcgacga caccggcgag caggagacacgatcccgtgc 240 atcttccagg ctgtggcccg gcgacaacca gagcgcctgg cactggtggacgccagtagt 300 ggtatatgct ggaccttcgc acagctggac acctactcca atgctgtagccaacctgttc 360 cgccagctgg gctttgcacc aggcgatgtg gtggctgtgt tcctggagggccggccggag 420 ttcgtgggac tgtggctggg cctggccaag gccggtgtgg tggctgctcttctcaatgtc 480 aacctgaggc gggagcccct ggccttctgc ctgggcacat cagctgccaaggccctcatt 540 tatggcgggg agatggcagc ggcggtggcg gaggtgagcg agcagctggggaagagcctc 600 ctcaagttct gctctggaga tctggggcct gagagcatcc tgcctgacacgcagctcctg 660 gaccccatgc ttgctgaggc gcccaccaca cccctggcac aagccccaggcaagggcatg 720 gatgatcggc tgttttacat ctatacttct gggaccaccg ggcttcctaaggctgccatt 780 gtggtgcaca gcaggtacta ccgcattgct gcctttggcc accattcctacagcatgcgt 840 gccgccgatg tgctctatga ctgcctgcca ctctaccact ctgcagggaacatcatgggt 900 gtggggcagt gcgtcatcta cgggttgacg gtggtactgc gcaagaagttctccgccagc 960 cgcttctggg atgactgtgt caagtacaat tgcacggtag tggatgacataggtgaaatc 1020 tgccgctacc tgctgaggca gccggttcgc gacgtggagc agcgacaccgcgtgcgcctg 1080 gccgtgggta atgggctgcg gccagccatc tgggaggagt tcacgcagcgcttcggtgtg 1140 ccacagatcg gcgagttcta cggcgctacc gagtgcaact gcagcattgccaacatggac 1200 ggcaaggtcg gctcctgcgg cttcaacagc cgtatcctca cgcatgtgtaccccatccgt 1260 ctggtcaagg tcaatgagga cacgatggag ccactgcggg actccgagggcctctgcatc 1320 ccgtgccagc ccggggaacc cggccttctc gtgggccaga tcaaccagcaggaccctctg 1380 cggcgtttcg atggttatgt tagtgacagt gccaccaaca agaagattgcccacagcgtt 1440 ttccgaaagg gcgatagcgc ctacctctca ggtgacgtgc tagtgatggacgagctgggc 1500 tacatgtatt tccgtgaccg cagcggggac accttccgct ggcgcggggagaacgtgtcc 1560 accacggagg tggaagccgt gctgagccgc ctactgggcc agacggacgtggctgtgtat 1620 ggggtggctg tgccaggagt ggaggggaaa gctggcatgg cagccatcgcagatccccac 1680 agccagttgg accctaactc aatgtaccag gaattacaga aggttcttgcatcctatgct 1740 cggcccatct tcctgcgtct tctgccccag gtggatacca caggcaccttcaagatccag 1800 aagacccggc tgcagcgtga aggctttgac ccccgtcaga cctcagacaggctcttcttt 1860 ctagacctga agtccggcac gaggtatcta cccctggatg agagagtccatgcccgcatt 1920 tgcgcaggcg acttctcact ctgagcctgg agagtgggct gggcctggactcctgagacc 1980 tgggagcctg acacccctct tcgggtgctt ctcctgcctg gccacatggacagcagcacc 2040 tgtgagagta ggaaaatgga acctgagtgg ctgggacccc tctcctacttcccactatgc 2100 atccattttg cctctgcctt gatctttttc tccatctctt ttctccctacccagcaggag 2160 ccccacaaac acatgttggc tgctgtgtcc tgcagttgga ccagtgtccaggggtacagg 2220 cttcaggctg tgacccacac tggtacccac ctccctttcc tattttgccttaggttcatc 2280 cacggttccc ctgtggagca agtgggggcc cacatagctg ctgtccctgctgagggttgg 2340 tagcaatcac accctcatgt cagctgggag acacgcgcag tctcccactgacccccaatc 2400 aactgaaaat attgttttga ctactttttg tttttttgtt tttttgtttttttttttttt 2460 cgagacagag tttctctgta tagccctggc tgtcctggaa ctcactttgtagaccaggct 2520 ggcctcgaac tcaaaaatcc tcctgactct gcctctgctt cccaagtgctgggattaaag 2580 acgtgcgcca ccaccgcctg gctgttttgt atttttgttt tgttttgacgatagggtctc 2640 actgtggagg ccaagctggc ctcagactcc ccaccccatt gcctctgggcaccattctat 2700 attctcagac tgatgacaat gcactagtgt ccctaggagt cttgagtctgcactttcccc 2760 tcatagcctc aagcttccag aactgactct gatcacttgg atgtggctagtgttggctct 2820 acccacatgt gtcaattcag gggtccccag gcatagtctc tggaagccctcacccggaaa 2880 aagcttggag agacccagga aggttgttgt gttctcttgg gcaccccctggtggcagtcc 2940 tgggcatgct tccgcactgt actggtgcat atagcccaga cctatgacatttgaggtcta 3000 cccttctggc tcctgtggtc cccattgaga tccttggtga ctcacctcagtcaccaagca 3060 gagcctctgc ctgccttcat cttcaaggtc atgaaggatg tggacagagcagctacaggc 3120 tgccagcagt caaccacatg agagtgttac ttccttgttg gtttttaaaaaataaatgtg 3180 ctgagcctcg aaaaaaaaaa aaaaaaaaaa aaaaaaa 3217 <210> SEQID NO 65 <211> LENGTH: 647 <212> TYPE: PRT <213> ORGANISM: Mus musculus<400> SEQUENCE: 65 Met Arg Ala Pro Gly Ala Gly Thr Ala Ser Val Ala SerLeu Ala Leu 1 5 10 15 Leu Trp Phe Leu Gly Leu Pro Trp Thr Trp Ser AlaAla Ala Ala Phe 20 25 30 Cys Val Tyr Val Gly Gly Gly Gly Trp Arg Phe LeuArg Ile Val Cys 35 40 45 Lys Thr Ala Arg Arg Asp Leu Phe Gly Leu Ser ValLeu Ile Arg Val 50 55 60 Arg Leu Glu Leu Arg Arg His Arg Arg Ala Gly AspThr Ile Pro Cys 65 70 75 80 Ile Phe Gln Ala Val Ala Arg Arg Gln Pro GluArg Leu Ala Leu Val 85 90 95 Asp Ala Ser Ser Gly Ile Cys Trp Thr Phe AlaGln Leu Asp Thr Tyr 100 105 110 Ser Asn Ala Val Ala Asn Leu Phe Arg GlnLeu Gly Phe Ala Pro Gly 115 120 125 Asp Val Val Ala Val Phe Leu Glu GlyArg Pro Glu Phe Val Gly Leu 130 135 140 Trp Leu Gly Leu Ala Lys Ala GlyVal Val Ala Ala Leu Leu Asn Val 145 150 155 160 Asn Leu Arg Arg Glu ProLeu Ala Phe Cys Leu Gly Thr Ser Ala Ala 165 170 175 Lys Ala Leu Ile TyrGly Gly Glu Met Ala Ala Ala Val Ala Glu Val 180 185 190 Ser Glu Gln LeuGly Lys Ser Leu Leu Lys Phe Cys Ser Gly Asp Leu 195 200 205 Gly Pro GluSer Ile Leu Pro Asp Thr Gln Leu Leu Asp Pro Met Leu 210 215 220 Ala GluAla Pro Thr Thr Pro Leu Ala Gln Ala Pro Gly Lys Gly Met 225 230 235 240Asp Asp Arg Leu Phe Tyr Ile Tyr Thr Ser Gly Thr Thr Gly Leu Pro 245 250255 Lys Ala Ala Ile Val Val His Ser Arg Tyr Tyr Arg Ile Ala Ala Phe 260265 270 Gly His His Ser Tyr Ser Met Arg Ala Ala Asp Val Leu Tyr Asp Cys275 280 285 Leu Pro Leu Tyr His Ser Ala Gly Asn Ile Met Gly Val Gly GlnCys 290 295 300 Val Ile Tyr Gly Leu Thr Val Val Leu Arg Lys Lys Phe SerAla Ser 305 310 315 320 Arg Phe Trp Asp Asp Cys Val Lys Tyr Asn Cys ThrVal Val Asp Asp 325 330 335 Ile Gly Glu Ile Cys Arg Tyr Leu Leu Arg GlnPro Val Arg Asp Val 340 345 350 Glu Gln Arg His Arg Val Arg Leu Ala ValGly Asn Gly Leu Arg Pro 355 360 365 Ala Ile Trp Glu Glu Phe Thr Gln ArgPhe Gly Val Pro Gln Ile Gly 370 375 380 Glu Phe Tyr Gly Ala Thr Glu CysAsn Cys Ser Ile Ala Asn Met Asp 385 390 395 400 Gly Lys Val Gly Ser CysGly Phe Asn Ser Arg Ile Leu Thr His Val 405 410 415 Tyr Pro Ile Arg LeuVal Lys Val Asn Glu Asp Thr Met Glu Pro Leu 420 425 430 Arg Asp Ser GluGly Leu Cys Ile Pro Cys Gln Pro Gly Glu Pro Gly 435 440 445 Leu Leu ValGly Gln Ile Asn Gln Gln Asp Pro Leu Arg Arg Phe Asp 450 455 460 Gly TyrVal Ser Asp Ser Ala Thr Asn Lys Lys Ile Ala His Ser Val 465 470 475 480Phe Arg Lys Gly Asp Ser Ala Tyr Leu Ser Gly Asp Val Leu Val Met 485 490495 Asp Glu Leu Gly Tyr Met Tyr Phe Arg Asp Arg Ser Gly Asp Thr Phe 500505 510 Arg Trp Arg Gly Glu Asn Val Ser Thr Thr Glu Val Glu Ala Val Leu515 520 525 Ser Arg Leu Leu Gly Gln Thr Asp Val Ala Val Tyr Gly Val AlaVal 530 535 540 Pro Gly Val Glu Gly Lys Ala Gly Met Ala Ala Ile Ala AspPro His 545 550 555 560 Ser Gln Leu Asp Pro Asn Ser Met Tyr Gln Glu LeuGln Lys Val Leu 565 570 575 Ala Ser Tyr Ala Arg Pro Ile Phe Leu Arg LeuLeu Pro Gln Val Asp 580 585 590 Thr Thr Gly Thr Phe Lys Ile Gln Lys ThrArg Leu Gln Arg Glu Gly 595 600 605 Phe Asp Pro Arg Gln Thr Ser Asp ArgLeu Phe Phe Leu Asp Leu Lys 610 615 620 Ser Gly Thr Arg Tyr Leu Pro LeuAsp Glu Arg Val His Ala Arg Ile 625 630 635 640 Cys Ala Gly Asp Phe SerLeu 645 <210> SEQ ID NO 66 <211> LENGTH: 2338 <212> TYPE: DNA <213>ORGANISM: Mus musculus <400> SEQUENCE: 66 gggcggaggc cgagcccagtcgccagctcc tgctctgctc ctctcccgcc tgccgccgcg 60 ctgcacgcct cgagcactccctcggccccg gcggggaccg gggaccccgc agctaccgcc 120 atgctgccag tgctctacaccggcctggcg gggctgctgc tgctgcctct gctgctcacc 180 tgctgctgcc cctacctcctccaagatgtg cggtacttcc tgcggctggc caacatggcc 240 cggcgggtgc gcagctaccggcagcggcga cccgtgcgta ccatcctgcg ggccttcctg 300 gaacaagcgc gcaagaccccacacaagccc ttcctgctgt tccgagacga gacgctcacc 360 tacgcccagg tggaccggcgcagcaaccaa gtggcgcggg cgctgcacga tcaactgggc 420 ctacgacagg gggattgcgtagccctcttc atgggcaatg agccggccta cgtgtggatc 480 tggctgggac tgctcaaactgggctgtccc atggcgtgcc tcaactacaa cattcgtgcc 540 aagtctctgc tgcactgctttcaatgctgc ggggcgaagg tgctgctggc ctccccagat 600 ctacaagaag ctgtggaggaggttcttcca accctgaaaa aggatgccgt gtccgtcttt 660 tacgtaagca gaacttctaacacaaatggt gtggacacaa tactggacaa agtagacgga 720 gtgtcggcgg aacccaccccggagtcgtgg aggtctgaag tcacttttac cacgccagca 780 gtatacattt atacttcgggaaccacaggt cttccaaaaa gcggaaccat caatcatcat 840 cgcctaaggt atgggacaagccttgctatg tcgagtggga atcacggcca aggatgtcat 900 ctataccaac aatgcccctgttccaacagt gcaacgctca agatcggcct tcacggatgc 960 atcctgggtt ggggctactttaaccttggc ggggcaaatt ctcaagcaag ccaattttgg 1020 gaacgactgg caggaaatacaacgtcaacg gtcattcagt acattggtga actgcttcgg 1080 tacctgtgca acacaccgcagaaaccaaat gaccgggacc acaaagtgaa aaaagccctg 1140 ggaaatggct tacgaggagatgtgtggaga gagttcatca agagatttgg ggacatccac 1200 gtgtatgagt tctacgcatccactgaaggc aacattggat ttgtgaacta tccaaggaaa 1260 atcggtgctg tcgggagagcaaactaccta caaagaaaag ttgcaaggta tgagctgatc 1320 aagtatgacg tggagaaggacgagccggtc cgtgacgcaa atggatattg catcaaagtc 1380 cccaaaggtg aggttggactcttggtttgc aaaatcacac agctcacacc atttattggc 1440 tatgctggag gaaagacccagacagagaag aaaaaactca gagatgtctt taagaaaggc 1500 gacatctact tcaacagcggagacctcctg atgatcgacc gtgagaactt cgtctacttt 1560 cacgacaggg ttggagatactttccggtgg aaaggagaga acgtagctac cacagaagtc 1620 gctgacatcg tgggactggtagattttgtt gaagaagtga atgtgtatgg cgtgcctgtg 1680 ccaggtcatg agggtcgaattgggatggcc tccctcaaga tcaaagaaaa ctacgagttc 1740 aatggaaaga aactctttcaacacatcgcg gagtacctgc ccagttacgc gaggcctcgg 1800 ttcctgagga tacaagataccattgagatc actgggactt ttaaacaccg caaagtgacc 1860 ctgatggaag agggcttcaatcccacagtc atcaaagata ccttgtattt catggatgat 1920 gcagagaaaa catttgtgcccatgactgag aacatttata atgccataat tgataaaact 1980 ctgaagctct gaatattccctggtggttta gctcatgaca tttccagaaa gaaactcgat 2040 agacctcgca gagccacttcatacgtagaa tccaacttta acttgattga agactataag 2100 gtgcgatttt atttttaggaaattattcat taaaaggata gttttttttt ttttttttaa 2160 ttacacctga acctttgcaagtaaaaagat ttagagacaa ttatttttca atgtgcacct 2220 gccatttgtc cttgcaaactaagcttcttg gagagagggc cttatttttt taaagacata 2280 ataaactata ttaacactaaaaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaa 2338 <210> SEQ ID NO 67 <211>LENGTH: 623 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE:67 Met Leu Pro Val Leu Tyr Thr Gly Leu Ala Gly Leu Leu Leu Leu Pro 1 510 15 Leu Leu Leu Thr Cys Cys Cys Pro Tyr Leu Leu Gln Asp Val Arg Tyr 2025 30 Phe Leu Arg Leu Ala Asn Met Ala Arg Arg Val Arg Ser Tyr Arg Gln 3540 45 Arg Arg Pro Val Arg Thr Ile Leu Arg Ala Phe Leu Glu Gln Ala Arg 5055 60 Lys Thr Pro His Lys Pro Phe Leu Leu Phe Arg Asp Glu Thr Leu Thr 6570 75 80 Tyr Ala Gln Val Asp Arg Arg Ser Asn Gln Val Ala Arg Ala Leu His85 90 95 Asp Gln Leu Gly Leu Arg Gln Gly Asp Cys Val Ala Leu Phe Met Gly100 105 110 Asn Glu Pro Ala Tyr Val Trp Ile Trp Leu Gly Leu Leu Lys LeuGly 115 120 125 Cys Pro Met Ala Cys Leu Asn Tyr Asn Ile Arg Ala Lys SerLeu Leu 130 135 140 His Cys Phe Gln Cys Cys Gly Ala Lys Val Leu Leu AlaSer Pro Asp 145 150 155 160 Leu Gln Glu Ala Val Glu Glu Val Leu Pro ThrLeu Lys Lys Asp Ala 165 170 175 Val Ser Val Phe Tyr Val Ser Arg Thr SerAsn Thr Asn Gly Val Asp 180 185 190 Thr Ile Leu Asp Lys Val Asp Gly ValSer Ala Glu Pro Thr Pro Glu 195 200 205 Ser Trp Arg Ser Glu Val Thr PheThr Thr Pro Ala Val Tyr Ile Tyr 210 215 220 Thr Ser Gly Thr Thr Gly LeuPro Lys Ser Gly Thr Ile Asn His His 225 230 235 240 Arg Leu Arg Tyr GlyThr Ser Leu Ala Met Ser Ser Gly Asn His Gly 245 250 255 Gln Gly Cys HisLeu Tyr Gln Gln Cys Pro Cys Ser Asn Ser Ala Thr 260 265 270 Leu Lys IleGly Leu His Gly Cys Ile Leu Gly Trp Gly Tyr Phe Asn 275 280 285 Leu GlyGly Ala Asn Ser Gln Ala Ser Gln Phe Trp Glu Arg Leu Ala 290 295 300 GlyAsn Thr Thr Ser Thr Val Ile Gln Tyr Ile Gly Glu Leu Leu Arg 305 310 315320 Tyr Leu Cys Asn Thr Pro Gln Lys Pro Asn Asp Arg Asp His Lys Val 325330 335 Lys Lys Ala Leu Gly Asn Gly Leu Arg Gly Asp Val Trp Arg Glu Phe340 345 350 Ile Lys Arg Phe Gly Asp Ile His Val Tyr Glu Phe Tyr Ala SerThr 355 360 365 Glu Gly Asn Ile Gly Phe Val Asn Tyr Pro Arg Lys Ile GlyAla Val 370 375 380 Gly Arg Ala Asn Tyr Leu Gln Arg Lys Val Ala Arg TyrGlu Leu Ile 385 390 395 400 Lys Tyr Asp Val Glu Lys Asp Glu Pro Val ArgAsp Ala Asn Gly Tyr 405 410 415 Cys Ile Lys Val Pro Lys Gly Glu Val GlyLeu Leu Val Cys Lys Ile 420 425 430 Thr Gln Leu Thr Pro Phe Ile Gly TyrAla Gly Gly Lys Thr Gln Thr 435 440 445 Glu Lys Lys Lys Leu Arg Asp ValPhe Lys Lys Gly Asp Ile Tyr Phe 450 455 460 Asn Ser Gly Asp Leu Leu MetIle Asp Arg Glu Asn Phe Val Tyr Phe 465 470 475 480 His Asp Arg Val GlyAsp Thr Phe Arg Trp Lys Gly Glu Asn Val Ala 485 490 495 Thr Thr Glu ValAla Asp Ile Val Gly Leu Val Asp Phe Val Glu Glu 500 505 510 Val Asn ValTyr Gly Val Pro Val Pro Gly His Glu Gly Arg Ile Gly 515 520 525 Met AlaSer Leu Lys Ile Lys Glu Asn Tyr Glu Phe Asn Gly Lys Lys 530 535 540 LeuPhe Gln His Ile Ala Glu Tyr Leu Pro Ser Tyr Ala Arg Pro Arg 545 550 555560 Phe Leu Arg Ile Gln Asp Thr Ile Glu Ile Thr Gly Thr Phe Lys His 565570 575 Arg Lys Val Thr Leu Met Glu Glu Gly Phe Asn Pro Thr Val Ile Lys580 585 590 Asp Thr Leu Tyr Phe Met Asp Asp Ala Glu Lys Thr Phe Val ProMet 595 600 605 Thr Glu Asn Ile Tyr Asn Ala Ile Ile Asp Lys Thr Leu LysLeu 610 615 620 <210> SEQ ID NO 68 <211> LENGTH: 1998 <212> TYPE: DNA<213> ORGANISM: Mus musculus <400> SEQUENCE: 68 gaaagctctg agagcgggtgcagtctggcc tggcgtctcg cgtacctggc ccgggagcag 60 ccgacacaca ccttcctcatccacggcgcg cagcgcttta gctacgcgga ggctgagcgc 120 gagagcaacc ggattgctcgcgcctttctg cgcgcacggg gctggaccgg gggccgccga 180 ggctcgggca ggggcagcactgaggaaggc gcacgcgtgg cgcctccggc tggagatgcg 240 gctgctagag ggacgaccgcgccccctctg gcacccgggg cgaccgtggc gctgctcctc 300 ccagcgggcc cggatttcctttggatttgg ttcggactgg ccaaagctgg cctgcgcacg 360 gcctttgtgc ccaccgctttacgccgagga cccctgctgc actgcctccg cagctgcggt 420 gcgagtgcgc tcgtgctggccacagagttc ctggagtccc tggagccgga cctgccggcc 480 ttgagagcca tggggctccacctatgggcg acgggccctg aaactaatgt agctggaatc 540 agcaatttgc tatcggaagcagcagaccaa gtggatgagc cagtgccggg gtacctctct 600 gccccccaga acataatggacacctgcctg tacatcttca cctctggcac tactggcctg 660 cccaaggctg ctcgaatcagtcatctgaag gttctacagt gccagggatt ctaccatctg 720 tgtggagtcc accaggaggacgtgatctac ctcgcactcc cactgtacca catgtctggc 780 tcccttctgg gcattgtgggctgcttgggc attggggcca ccgtggtgct gaaacccaag 840 ttctcagcta gccagttctgggacgattgc cagaaacaca gggtgacagt gttccagtac 900 attggggagt tgtgccgatacctcgtcaac cagcccccga gcaaggcaga gtttgaccat 960 aaggtgcgct tggcagtgggcagtgggttg cgcccagaca cctgggagcg tttcctgcgg 1020 cgatttggac ctctgcagatactggagacg tatggcatga cagagggcaa cgtagctacg 1080 ttcaattaca caggacggcagggtgcagtg gggcgagctt cctggcttta caagcacatc 1140 ttccccttct ccttgattcgatacgatgtc atgacagggg agcctattcg gaatgcccag 1200 gggcactgca tgaccacatctccaggtgag ccaggcctac tggtggcccc agtgagccag 1260 cagtccccct tcctgggctatgctggggct ccggagctgg ccaaggacaa gctgctgaag 1320 gatgtcttct ggtctggggacgttttcttc aatactgggg acctcttggt ctgtgatgag 1380 caaggctttc ttcacttccacgatcgtact ggagacacca tcaggtggaa gggagagaat 1440 gtggccacaa ctgaagtggctgaggtcttg gagaccctgg acttccttca ggaggtgaac 1500 atctatggag tcacggtgccagggcacgaa ggcagggcag gcatggcggc cttggctctg 1560 cggcccccgc aggctctgaacctggtgcag ctctacagcc atgtttctga gaacttgcca 1620 ccgtatgccc gacctcggtttctcaggctc caggaatctt tggccactac tgagaccttc 1680 aaacagcaga aggttaggatggccaatgag ggctttgacc ccagtgtact gtctgaccca 1740 ctctatgttc tggaccaagatataggggcc tacctgcccc tcacacctgc ccggtacagt 1800 gccctcctgt ctggagaccttcgaatctga aaccttccac ttgagggagg ggctcggagg 1860 gtacaggcca ccatggctgcaccagggagg gttttcgggt atcttttgta tatggagtca 1920 ttattttgta ataaacagctggagcttaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 1980 aaaaaaaaaa aaaaaaaa1998 <210> SEQ ID NO 69 <211> LENGTH: 609 <212> TYPE: PRT <213>ORGANISM: Mus musculus <400> SEQUENCE: 69 Glu Ser Ser Glu Ser Gly CysSer Leu Ala Trp Arg Leu Ala Tyr Leu 1 5 10 15 Ala Arg Glu Gln Pro ThrHis Thr Phe Leu Ile His Gly Ala Gln Arg 20 25 30 Phe Ser Tyr Ala Glu AlaGlu Arg Glu Ser Asn Arg Ile Ala Arg Ala 35 40 45 Phe Leu Arg Ala Arg GlyTrp Thr Gly Gly Arg Arg Gly Ser Gly Arg 50 55 60 Gly Ser Thr Glu Glu GlyAla Arg Val Ala Pro Pro Ala Gly Asp Ala 65 70 75 80 Ala Ala Arg Gly ThrThr Ala Pro Pro Leu Ala Pro Gly Ala Thr Val 85 90 95 Ala Leu Leu Leu ProAla Gly Pro Asp Phe Leu Trp Ile Trp Phe Gly 100 105 110 Leu Ala Lys AlaGly Leu Arg Thr Ala Phe Val Pro Thr Ala Leu Arg 115 120 125 Arg Gly ProLeu Leu His Cys Leu Arg Ser Cys Gly Ala Ser Ala Leu 130 135 140 Val LeuAla Thr Glu Phe Leu Glu Ser Leu Glu Pro Asp Leu Pro Ala 145 150 155 160Leu Arg Ala Met Gly Leu His Leu Trp Ala Thr Gly Pro Glu Thr Asn 165 170175 Val Ala Gly Ile Ser Asn Leu Leu Ser Glu Ala Ala Asp Gln Val Asp 180185 190 Glu Pro Val Pro Gly Tyr Leu Ser Ala Pro Gln Asn Ile Met Asp Thr195 200 205 Cys Leu Tyr Ile Phe Thr Ser Gly Thr Thr Gly Leu Pro Lys AlaAla 210 215 220 Arg Ile Ser His Leu Lys Val Leu Gln Cys Gln Gly Phe TyrHis Leu 225 230 235 240 Cys Gly Val His Gln Glu Asp Val Ile Tyr Leu AlaLeu Pro Leu Tyr 245 250 255 His Met Ser Gly Ser Leu Leu Gly Ile Val GlyCys Leu Gly Ile Gly 260 265 270 Ala Thr Val Val Leu Lys Pro Lys Phe SerAla Ser Gln Phe Trp Asp 275 280 285 Asp Cys Gln Lys His Arg Val Thr ValPhe Gln Tyr Ile Gly Glu Leu 290 295 300 Cys Arg Tyr Leu Val Asn Gln ProPro Ser Lys Ala Glu Phe Asp His 305 310 315 320 Lys Val Arg Leu Ala ValGly Ser Gly Leu Arg Pro Asp Thr Trp Glu 325 330 335 Arg Phe Leu Arg ArgPhe Gly Pro Leu Gln Ile Leu Glu Thr Tyr Gly 340 345 350 Met Thr Glu GlyAsn Val Ala Thr Phe Asn Tyr Thr Gly Arg Gln Gly 355 360 365 Ala Val GlyArg Ala Ser Trp Leu Tyr Lys His Ile Phe Pro Phe Ser 370 375 380 Leu IleArg Tyr Asp Val Met Thr Gly Glu Pro Ile Arg Asn Ala Gln 385 390 395 400Gly His Cys Met Thr Thr Ser Pro Gly Glu Pro Gly Leu Leu Val Ala 405 410415 Pro Val Ser Gln Gln Ser Pro Phe Leu Gly Tyr Ala Gly Ala Pro Glu 420425 430 Leu Ala Lys Asp Lys Leu Leu Lys Asp Val Phe Trp Ser Gly Asp Val435 440 445 Phe Phe Asn Thr Gly Asp Leu Leu Val Cys Asp Glu Gln Gly PheLeu 450 455 460 His Phe His Asp Arg Thr Gly Asp Thr Ile Arg Trp Lys GlyGlu Asn 465 470 475 480 Val Ala Thr Thr Glu Val Ala Glu Val Leu Glu ThrLeu Asp Phe Leu 485 490 495 Gln Glu Val Asn Ile Tyr Gly Val Thr Val ProGly His Glu Gly Arg 500 505 510 Ala Gly Met Ala Ala Leu Ala Leu Arg ProPro Gln Ala Leu Asn Leu 515 520 525 Val Gln Leu Tyr Ser His Val Ser GluAsn Leu Pro Pro Tyr Ala Arg 530 535 540 Pro Arg Phe Leu Arg Leu Gln GluSer Leu Ala Thr Thr Glu Thr Phe 545 550 555 560 Lys Gln Gln Lys Val ArgMet Ala Asn Glu Gly Phe Asp Pro Ser Val 565 570 575 Leu Ser Asp Pro LeuTyr Val Leu Asp Gln Asp Ile Gly Ala Tyr Leu 580 585 590 Pro Leu Thr ProAla Arg Tyr Ser Ala Leu Leu Ser Gly Asp Leu Arg 595 600 605 Ile <210>SEQ ID NO 70 <211> LENGTH: 2710 <212> TYPE: DNA <213> ORGANISM: Musmusculus <400> SEQUENCE: 70 atgctgcttg gagcctctct ggtgggggcg ctactgttctccaagctagt gctgaagctg 60 ccctggaccc aggtgggatt ctccctgttg ctcctgtacttggggtctgg tggctggcgt 120 ttcatccggg tcttcatcaa gacggtcagg agagatatctttggtggcat ggtgctcctg 180 aaggtgaaga ccaaggtgcg acggtacctt caggagcggaagacggtgcc cctgctgttt 240 gcttcaatgg tacagcgcca cccggacaag acagccctgattttcgaggg cacagacact 300 cactggacct tccgccagct ggatgagtac tccagtagtgtggccaactt cctgcaggcc 360 cggggcctgg cctcaggcaa tgtagttgcc ctctttatggaaaaccgcaa tgagtttgtg 420 ggtctgtggc taggcatggc caagctgggc gtggaggcggctctcatcaa caccaacctt 480 aggcgggatg ccctgcgcca ctgtcttgac acctcaaaggcacgagctct catctttggc 540 agtgagatgg cctcagctat ctgtgagatc catgctagcctggagcccac actcagcctc 600 ttctgctctg gatcctggga gcccagcaca gtgcccgtcagcacagagca tctggaccct 660 cttctggaag atgccccgaa gcacctgccc agtcacccagacaagggttt tacagataag 720 ctcttctaca tctacacatc gggcaccacg gggctacccaaagctgccat tgtggtgcac 780 agcaggtatt atcgtatggc ttccctggtg tactatggattccgcatgcg gcctgatgac 840 attgtctatg actgcctccc cctctaccac tcaagcaggaaacatcgtgg ggattggcag 900 tgcttactcc acggcatgac tgtggtgatc cggaagaagttctcagcctc ccggttctgg 960 gatgattgta tcaagtacaa ctgcacagtg gtacagtacattggcgagct ctgccgctac 1020 tcctgaacc agccaccccg tgaggctgag tctcggcacaaggtgcgcat ggcactgggc 1080 acggtctcc ggcagtccat ctggaccgac ttctccagccgtttccacat cccccaggtg 1140 ctgagttct atggggccac tgaatgcaac tgtagcctgggcaactttga cagccgggtg 1200 gggcctgtg gcttcaatag ccgcatcctg tcctttgtgtaccctatccg tttggtacgt 1260 tcaatgagg ataccatgga actgatccgg ggacccgatggagtctgcat tccctgtcaa 1320 caggtcagc caggccagct ggtgggtcgc atcatccagcaggaccctct gcgccgtttc 1380 acgggtacc tcaaccaggg tgccaacaac aagaagattgctaatgatgt cttcaagaag 1440 gggaccaag cctacctcac tggtgacgtc ctggtgatggatgagctggg ttacctgtac 1500 tccgagatc gcactgggga cacgttccgc tggaaaggggagaatgtatc taccactgag 1560 tggagggca cactcagccg cctgcttcat atggcagatgtggcagttta tggtgttgag 1620 tgccaggaa ctgaaggccg agcaggaatg gctgccgttgcaagtcccat cagcaactgt 1680 acctggaga gctttgcaca gaccttgaaa aaggagctgcctctgtatgc ccgccccatc 1740 tcctgcgct tcttgcctga gctgcacaag acagggaccttcaagttcca gaagacagag 1800 tgcggaagg agggctttga cccatctgtt gtgaaagacccgctgttcta tctggatgct 1860 ggaagggct gctacgttgc actggaccag gaggcctatacccgcatcca ggcaggcgag 1920 agaagctgt gatttccccc tacatccctc tgagggccagaagatgctgg attcagagcc 1980 tagcgtcca ccccagaggg tcctgggcaa tgccagaccaaagctagcag ggcccgcacc 2040 ccgccccta ggtgctgatc tcccctctcc caaactgccaagtgactcac tgccgcttcc 2100 cgaccctcc agaggctttc tgtgaaagtc tcatccaagctgtgtcttct ggtccaggcg 2160 ggcccctgg ccccagggtt tctgataggc tcctttaggatggtatcttg ggtccagcgg 2220 ccagggtgt gggagaggag tcactaagat ccctccaatcagaagggagc ttacaaagga 2280 ccaaggcaa agcctgtaga ctcaggaagc taagtggccagagactatag tggccagtca 2340 cccatgtcc acagaggatc ttggtccaga gctgccaaagtgtcacctct ccctgcctgc 2400 cctctgggg aaaagaggac agcatgtggc cactgggcacctgtctcaag aagtcaggat 2460 acacactca gtccttgttt ctccaggttc ccttgttcttgtctcgggga gggagggacg 2520 gtgtcctgt ctgtccttcc tgcctgtctg tgagtctgtgttgcttctcc atctgtccta 2580 cctgagtgt gggtggaaca ggcatgagga gagtgtggctcaggggccaa taaactctgc 2640 ttgactcct cttaaaaaaa aaaaaaaaaa aaaaaaaaaaaaaaaaaaaa aaaaaaaaaa 2700 aaaaaaaaa 2710 <210> SEQ ID NO 71 <211>LENGTH: 643 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE:71 Met Leu Leu Gly Ala Ser Leu Val Gly Ala Leu Leu Gly Ser Lys Leu 1 510 15 Val Leu Lys Leu Pro Trp Thr Gln Val Gly Phe Ser Leu Leu Leu Leu 2025 30 Tyr Leu Gly Ser Gly Gly Trp Arg Phe Ile Arg Val Phe Ile Lys Thr 3540 45 Val Arg Arg Asp Ile Phe Gly Gly Met Val Leu Leu Lys Val Lys Thr 5055 60 Lys Val Arg Arg Tyr Leu Gln Glu Arg Lys Thr Val Pro Leu Leu Phe 6570 75 80 Ala Ser Met Val Gln Arg His Pro Asp Lys Thr Ala Leu Ile Phe Glu85 90 95 Gly Thr Asp Thr His Trp Thr Phe Arg Gln Leu Asp Glu Tyr Ser Ser100 105 110 Ser Val Ala Asn Phe Leu Gln Ala Arg Gly Leu Ala Ser Gly AsnVal 115 120 125 Val Ala Leu Phe Met Glu Asn Arg Asn Glu Phe Val Gly LeuTrp Leu 130 135 140 Gly Met Ala Lys Leu Gly Val Glu Ala Ala Leu Ile AsnThr Asn Leu 145 150 155 160 Arg Arg Asp Ala Leu Arg His Cys Leu Asp ThrSer Lys Ala Arg Ala 165 170 175 Leu Ile Phe Gly Ser Glu Met Ala Ser AlaIle Cys Glu Ile His Ala 180 185 190 Ser Leu Glu Pro Thr Leu Ser Leu PheCys Ser Gly Ser Trp Glu Pro 195 200 205 Ser Thr Val Pro Val Ser Thr GluHis Leu Asp Pro Leu Leu Glu Asp 210 215 220 Ala Pro Lys His Leu Pro SerHis Pro Asp Lys Gly Phe Thr Asp Lys 225 230 235 240 Leu Phe Tyr Ile TyrThr Ser Gly Thr Thr Gly Leu Pro Lys Ala Ala 245 250 255 Ile Val Val HisSer Arg Tyr Tyr Arg Met Ala Ser Leu Val Tyr Tyr 260 265 270 Gly Phe ArgMet Arg Pro Asp Asp Ile Val Tyr Asp Cys Leu Pro Leu 275 280 285 Tyr HisSer Ser Arg Lys His Arg Gly Asp Trp Gln Cys Leu Leu His 290 295 300 GlyMet Thr Val Val Ile Arg Lys Lys Phe Ser Ala Ser Arg Phe Trp 305 310 315320 Asp Asp Cys Ile Lys Tyr Asn Cys Thr Val Val Gln Tyr Ile Gly Glu 325330 335 Leu Cys Arg Tyr Leu Leu Asn Gln Pro Pro Arg Glu Ala Glu Ser Arg340 345 350 His Lys Val Arg Met Ala Leu Gly Asn Gly Leu Arg Gln Ser IleTrp 355 360 365 Thr Asp Phe Ser Ser Arg Phe His Ile Pro Gln Val Ala GluPhe Tyr 370 375 380 Gly Ala Thr Glu Cys Asn Cys Ser Leu Gly Asn Phe AspSer Arg Val 385 390 395 400 Gly Ala Cys Gly Phe Asn Ser Arg Ile Leu SerPhe Val Tyr Pro Ile 405 410 415 Arg Leu Val Arg Val Asn Glu Asp Thr MetGlu Leu Ile Arg Gly Pro 420 425 430 Asp Gly Val Cys Ile Pro Cys Gln ProGly Gln Pro Gly Gln Leu Val 435 440 445 Gly Arg Ile Ile Gln Gln Asp ProLeu Arg Arg Phe Asp Gly Tyr Leu 450 455 460 Asn Gln Gly Ala Asn Asn LysLys Ile Ala Asn Asp Val Phe Lys Lys 465 470 475 480 Gly Asp Gln Ala TyrLeu Thr Gly Asp Val Leu Val Met Asp Glu Leu 485 490 495 Gly Tyr Leu TyrPhe Arg Asp Arg Thr Gly Asp Thr Phe Arg Trp Lys 500 505 510 Gly Glu AsnVal Ser Thr Thr Glu Val Glu Gly Thr Leu Ser Arg Leu 515 520 525 Leu HisMet Ala Asp Val Ala Val Tyr Gly Val Glu Val Pro Gly Thr 530 535 540 GluGly Arg Ala Gly Met Ala Ala Val Ala Ser Pro Ile Ser Asn Cys 545 550 555560 Asp Leu Glu Ser Phe Ala Gln Thr Leu Lys Lys Glu Leu Pro Leu Tyr 565570 575 Ala Arg Pro Ile Phe Leu Arg Phe Leu Pro Glu Leu His Lys Thr Gly580 585 590 Thr Phe Lys Phe Gln Lys Thr Glu Leu Arg Lys Glu Gly Phe AspPro 595 600 605 Ser Val Val Lys Asp Pro Leu Phe Tyr Leu Asp Ala Arg LysGly Cys 610 615 620 Tyr Val Ala Leu Asp Gln Glu Ala Tyr Thr Arg Ile GlnAla Gly Glu 625 630 635 640 Glu Lys Leu <210> SEQ ID NO 72 <211> LENGTH:2277 <212> TYPE: DNA <213> ORGANISM: Mus musculus <400> SEQUENCE: 72cactcatcag agctaagaga gactacacgc tctcatctac ttcagaaaga gccaatgcca 60tgggtatttg gaagaaacta accttactgc tgttgctgct tctgctggtt ggcctggggc 120agcccccatg gccagcagct atggctctgg ccctgcgttg gttcctggga gaccccacat 180gccttgtgct gcttggcttg gcattgctgg gcagaccctg gatcagctcc tggatgcccc 240actggctgag cctggtagga gcagctctta ccttattcct attgcctcta cagccacccc 300cagggctacg ctggctgcat aaagatgtgg ctttcacctt caagatgctt ttctatggcc 360taaagttcag gcgacgcctt aacaaacatc ctccagagac ctttgtggat gctttagagc 420ggcaagcact ggcatggcct gaccgggtgg ccttggtgtg tactgggtct gagggctcct 480caatcacaaa tagccagctg gatgccaggt cctgtcaggc agcatgggtc ctgaaagcaa 540agctgaagga tgccgtaatc cagaacacaa gagatgctgc tgctatctta gttctcccgt 600ccaagaccat ttctgctttg agtgtgtttc tggggttggc caagttgggc tgccctgtgg 660cctggatcaa tccacacagc cgagggatgc ccttgctaca ctctgtacgg agctctgggg 720ccagtgtgct gattgtggat ccagacctcc aggagaacct ggaagaagtc cttcccaagc 780tgctagctga gaacattcac tgcttctacc ttggccacag ctcacccacc ccgggagtag 840aggctctggg agcttccctg gatgctgcac cttctgaccc agtacctgcc agccttcgag 900ctacgattaa gtggaaatct cctgccatat tcatctttac ttcagggacc actggactcc 960aaagccagc catcttatca catgagcggg tcatacaagt gagcaacgtg ctgtccttct 1020tggatgcag agctgatgat gtggtctatg acgtcctacc tctgtaccat acgatagggc 1080tgtccttgg attccttggc tgcttacaag ttggagccac ctgtgtcctg gcccccaagt 1140ctctgcctc ccgattctgg gctgagtgcc ggcagcatgg cgtaacagtg atcttgtatg 1200gggtgaaat cctgcggtac ttgtgtaacg tccctgagca accagaagac aagatacata 1260agtgcgctt ggccatggga actggacttc gggcaaatgt gtggaaaaac ttccagcaac 1320ctttggtcc cattcggatc tgggaattct acggatccac agagggcaat gtgggcttaa 1380gaactatgt gggccactgc ggggctgtgg gaaggaccag ctgcatcctt cgaatgctga 1440tccctttga gcttgtacag ttcgacatag agacagcaga gcctctgagg gacaaacagg 1500tttttgcat tcctgtggag ccaggaaagc caggacttct tttgaccaag gttcgaaaga 1560ccaaccctt cctgggctac cgtggttccc aggccgagtc caatcggaaa cttgttgcga 1620tgtacgacg cgtaggagac ctgtacttca acactgggga cgtgctgacc ttggaccagg 1680aggcttctt ctactttcaa gaccgccttg gtgacacctt ccggtggaag ggcgaaaacg 1740atctactgg agaggtggag tgtgttttgt ctagcctaga cttcctagag gaagtcaatg 1800ctatggtgt gcctgtgcca gggtgtgagg gtaaggttgg catggctgct gtgaaactgg 1860tcctgggaa gacttttgat gggcagaagc tataccagca tgtccgctcc tggctccctg 1920ctatgccac acctcatttc atccgtatcc aggattccct ggagatcaca aacacctaca 1980gctggtaaa gtcacggctg gtgcgtgagg gttttgatgt ggggatcatt gctgaccccc 2040ctacatact ggacaacaag gcccagacct tccggagtct gatgccagat gtgtaccagg 2100tgtgtgtga aggaacctgg aatctctgac cacctagcca actggaaggc aatccaaaag 2160gtagagatt gacactagtc agcttcacaa agttgtccgg gttccagatg cccatggccc 2220gtagtactt agagaataaa cttgaatgtg tatacaaaaa aaaaaaaaaa aaaaaaa 2277 <210>SEQ ID NO 73 <211> LENGTH: 689 <212> TYPE: PRT <213> ORGANISM: Musmusculus <400> SEQUENCE: 73 Met Gly Ile Trp Lys Lys Leu Thr Leu Leu LeuLeu Leu Leu Leu Leu 1 5 10 15 Val Gly Leu Gly Gln Pro Pro Trp Pro AlaAla Met Ala Leu Ala Leu 20 25 30 Arg Trp Phe Leu Gly Asp Pro Thr Cys LeuVal Leu Leu Gly Leu Ala 35 40 45 Leu Leu Gly Arg Pro Trp Ile Ser Ser TrpMet Pro His Trp Leu Ser 50 55 60 Leu Val Gly Ala Ala Leu Thr Leu Phe LeuLeu Pro Leu Gln Pro Pro 65 70 75 80 Pro Gly Leu Arg Trp Leu His Lys AspVal Ala Phe Thr Phe Lys Met 85 90 95 Leu Phe Tyr Gly Leu Lys Phe Arg ArgArg Leu Asn Lys His Pro Pro 100 105 110 Glu Thr Phe Val Asp Ala Leu GluArg Gln Ala Leu Ala Trp Pro Asp 115 120 125 Arg Val Ala Leu Val Cys ThrGly Ser Glu Gly Ser Ser Ile Thr Asn 130 135 140 Ser Gln Leu Asp Ala ArgSer Cys Gln Ala Ala Trp Val Leu Lys Ala 145 150 155 160 Lys Leu Lys AspAla Val Ile Gln Asn Thr Arg Asp Ala Ala Ala Ile 165 170 175 Leu Val LeuPro Ser Lys Thr Ile Ser Ala Leu Ser Val Phe Leu Gly 180 185 190 Leu AlaLys Leu Gly Cys Pro Val Ala Trp Ile Asn Pro His Ser Arg 195 200 205 GlyMet Pro Leu Leu His Ser Val Arg Ser Ser Gly Ala Ser Val Leu 210 215 220Ile Val Asp Pro Asp Leu Gln Glu Asn Leu Glu Glu Val Leu Pro Lys 225 230235 240 Leu Leu Ala Glu Asn Ile His Cys Phe Tyr Leu Gly His Ser Ser Pro245 250 255 Thr Pro Gly Val Glu Ala Leu Gly Ala Ser Leu Asp Ala Ala ProSer 260 265 270 Asp Pro Val Pro Ala Ser Leu Arg Ala Thr Ile Lys Trp LysSer Pro 275 280 285 Ala Ile Phe Ile Phe Thr Ser Gly Thr Thr Gly Leu ProLys Pro Ala 290 295 300 Ile Leu Ser His Glu Arg Val Ile Gln Val Ser AsnVal Leu Ser Phe 305 310 315 320 Cys Gly Cys Arg Ala Asp Asp Val Val TyrAsp Val Leu Pro Leu Tyr 325 330 335 His Thr Ile Gly Leu Val Leu Gly PheLeu Gly Cys Leu Gln Val Gly 340 345 350 Ala Thr Cys Val Leu Ala Pro LysPhe Ser Ala Ser Arg Phe Trp Ala 355 360 365 Glu Cys Arg Gln His Gly ValThr Val Ile Leu Tyr Val Gly Glu Ile 370 375 380 Leu Arg Tyr Leu Cys AsnVal Pro Glu Gln Pro Glu Asp Lys Ile His 385 390 395 400 Thr Val Arg LeuAla Met Gly Thr Gly Leu Arg Ala Asn Val Trp Lys 405 410 415 Asn Phe GlnGln Arg Phe Gly Pro Ile Arg Ile Trp Glu Phe Tyr Gly 420 425 430 Ser ThrGlu Gly Asn Val Gly Leu Met Asn Tyr Val Gly His Cys Gly 435 440 445 AlaVal Gly Arg Thr Ser Cys Ile Leu Arg Met Leu Thr Pro Phe Glu 450 455 460Leu Val Gln Phe Asp Ile Glu Thr Ala Glu Pro Leu Arg Asp Lys Gln 465 470475 480 Gly Phe Cys Ile Pro Val Glu Pro Gly Lys Pro Gly Leu Leu Leu Thr485 490 495 Lys Val Arg Lys Asn Gln Pro Phe Leu Gly Tyr Arg Gly Ser GlnAla 500 505 510 Glu Ser Asn Arg Lys Leu Val Ala Asn Val Arg Arg Val GlyAsp Leu 515 520 525 Tyr Phe Asn Thr Gly Asp Val Leu Thr Leu Asp Gln GluGly Phe Phe 530 535 540 Tyr Phe Gln Asp Arg Leu Gly Asp Thr Phe Arg TrpLys Gly Glu Asn 545 550 555 560 Val Ser Thr Gly Glu Val Glu Cys Val LeuSer Ser Leu Asp Phe Leu 565 570 575 Glu Glu Val Asn Val Tyr Gly Val ProVal Pro Gly Cys Glu Gly Lys 580 585 590 Val Gly Met Ala Ala Val Lys LeuAla Pro Gly Lys Thr Phe Asp Gly 595 600 605 Gln Lys Leu Tyr Gln His ValArg Ser Trp Leu Pro Ala Tyr Ala Thr 610 615 620 Pro His Phe Ile Arg IleGln Asp Ser Leu Glu Ile Thr Asn Thr Tyr 625 630 635 640 Lys Leu Val LysSer Arg Leu Val Arg Glu Gly Phe Asp Val Gly Ile 645 650 655 Ile Ala AspPro Leu Tyr Ile Leu Asp Asn Lys Ala Gln Thr Phe Arg 660 665 670 Ser LeuMet Pro Asp Val Tyr Gln Ala Val Cys Glu Gly Thr Trp Asn 675 680 685 Leu<210> SEQ ID NO 74 <211> LENGTH: 2221 <212> TYPE: DNA <213> ORGANISM:Drosophila melanogaster <400> SEQUENCE: 74 gctctctggg cctatatcaagctgctgagg tacacgaagc gccatgagcg gctcaactac 60 acggtggcgg acgtcttcgaacgaaatgtt caggcccatc cggacaaggt ggctgtggtc 120 agtgagacgc aacgctggaccttccgtcag gtgaacgagc atgcgaacaa ggtggccaat 180 gtgctgcagg ctcagggctacaaaaagggc gatgtggtgg ccctgttgct ggagaaccgc 240 gccgagtacg tggccacctggctgggtctc tccaagatcg gtgtgatcac accgctgatc 300 aacacgaatc tgcgcggtccctccctgctg cacagcatca cggtggccca ttgctcggct 360 ctcatttacg gcgaggacttcctggaagct gtcaccgacg tggccaagga tctgccagcg 420 aacctcacac tcttccagttcaacaacgag aacaacaaca gcgagacgga aaagaacata 480 ccgcaggcca agaatctgaacgcgctgctg accacggcca gctatgagaa gcctaacaag 540 acgcaggtta accaccacgacaagctggtc tacatctaca cctccggcac cacaggattg 600 ccaaaggctg cggttatctctcactcccgt tatctgttta tcgctgctgg catccactac 660 accatgggtt tccaggaggaggacatcttc tacacgccct tgcctttgta ccacaccgct 720 ggtggcatta tgtgcatgggtcagtcggtg ctctttggct ccacggtctc cattcgcaag 780 aagttctcgg catccaactatttcgccgac tgcgccaagt ataatgcaac tattggtcag 840 tatatcggtg agatggctcgctacattcta gctacgaaac cctcggaata cgaccagaaa 900 caccgagtgc gtctggtctttggaaacgga ctgcgaccgc agatttggcc acagtttgtg 960 cagcgcttca acattgccaaggttggcgag ttctacggcg ccaccgaggg taatgcgaac 1020 atcatgaatc atgacaacacggtgggcgcc atcggctttg tgtcgcgcat cctgcccaag 1080 atctacccaa tctcgatcattcgcgccgat ccggacaccg gagagcccat tagagatagg 1140 aatggcctat gccaactgtgcgctcccaac gagccaggcg tattcatcgg caagatcgtc 1200 aaaggaaatc cttctcgcgaattcctcgga tacgtcgatg aaaaggcctc cgcgaagaag 1260 attgttaagg atgtgttcaagcatggcgat atggctttca tctccggaga tctgctggtt 1320 gccgacgaga agggttatctgtacttcaag gatcgcaccg gtgacacctt ccgctggaag 1380 ggcgagaatg tttccaccagcgaggtggag gcgcaagtca gcaatgtggc cggttacaag 1440 gataccgtcg tttacggcgtaaccattccg cacaccgagg gaagggccgg catggccgcc 1500 atctatgatc cggagcgagaattggacctc gacgtcttcg ccgctagctt ggccaaggtg 1560 ctgcccgcgt acgctcgtccccagatcatt cgattgctca ccaaggtgga cctgactgga 1620 acctttaagc tgcgcaaggtagacctgcag aaggagggct acgatccgaa cgcgatcaag 1680 gacgcgctgt actaccagacttccaagggt cggtacgagc tgctcacgcc ccaggtttac 1740 gaccaggtgc agcgcaacgaaatccgcttc taagagctgc aatagagttg tgtctgaacc 1800 ttgccttttg cccaatatgctgttaattag tttgtaaggc taagtgtagt agaggaaaat 1860 cgggggaaat cggcagcaaagatcattcag cctaggagag atgcatccga agcacatttc 1920 catgtcaaca atgcacttttgtatatcgta agcatatata tatcgtatat cgtaaacgta 1980 gttgtatctg catttgtgtagatgatagcc tcctatacgc atttcaattg tttttagcgt 2040 gctaaagaac cttgttaaatgcaatttcag ctattgttta gtcagtttta gtggcattta 2100 cacttccatt ctcgttgcgtttcgtttttg cctgtacata tgagaagctc tgatgttttt 2160 gtatcaaata aagttttttccttcaccacg gaccacgtga aaaaaaaaaa aaaaaaaaaa 2220 a 2221 <210> SEQ ID NO75 <211> LENGTH: 590 <212> TYPE: PRT <213> ORGANISM: Drosophilamelanogaster <400> SEQUENCE: 75 Ala Leu Trp Ala Tyr Ile Lys Leu Leu ArgTyr Thr Lys Arg His Glu 1 5 10 15 Arg Leu Asn Tyr Thr Val Ala Asp ValPhe Glu Arg Asn Val Gln Ala 20 25 30 His Pro Asp Lys Val Ala Val Val SerGlu Thr Gln Arg Trp Thr Phe 35 40 45 Arg Gln Val Asn Glu His Ala Asn LysVal Ala Asn Val Leu Gln Ala 50 55 60 Gln Gly Tyr Lys Lys Gly Asp Val ValAla Leu Leu Leu Glu Asn Arg 65 70 75 80 Ala Glu Tyr Val Ala Thr Trp LeuGly Leu Ser Lys Ile Gly Val Ile 85 90 95 Thr Pro Leu Ile Asn Thr Asn LeuArg Gly Pro Ser Leu Leu His Ser 100 105 110 Ile Thr Val Ala His Cys SerAla Leu Ile Tyr Gly Glu Asp Phe Leu 115 120 125 Glu Ala Val Thr Asp ValAla Lys Asp Leu Pro Ala Asn Leu Thr Leu 130 135 140 Phe Gln Phe Asn AsnGlu Asn Asn Asn Ser Glu Thr Glu Lys Asn Ile 145 150 155 160 Pro Gln AlaLys Asn Leu Asn Ala Leu Leu Thr Thr Ala Ser Tyr Glu 165 170 175 Lys ProAsn Lys Thr Gln Val Asn His His Asp Lys Leu Val Tyr Ile 180 185 190 TyrThr Ser Gly Thr Thr Gly Leu Pro Lys Ala Ala Val Ile Ser His 195 200 205Ser Arg Tyr Leu Phe Ile Ala Ala Gly Ile His Tyr Thr Met Gly Phe 210 215220 Gln Glu Glu Asp Ile Phe Tyr Thr Pro Leu Pro Leu Tyr His Thr Ala 225230 235 240 Gly Gly Ile Met Cys Met Gly Gln Ser Val Leu Phe Gly Ser ThrVal 245 250 255 Ser Ile Arg Lys Lys Phe Ser Ala Ser Asn Tyr Phe Ala AspCys Ala 260 265 270 Lys Tyr Asn Ala Thr Ile Gly Gln Tyr Ile Gly Glu MetAla Arg Tyr 275 280 285 Ile Leu Ala Thr Lys Pro Ser Glu Tyr Asp Gln LysHis Arg Val Arg 290 295 300 Leu Val Phe Gly Asn Gly Leu Arg Pro Gln IleTrp Pro Gln Phe Val 305 310 315 320 Gln Arg Phe Asn Ile Ala Lys Val GlyGlu Phe Tyr Gly Ala Thr Glu 325 330 335 Gly Asn Ala Asn Ile Met Asn HisAsp Asn Thr Val Gly Ala Ile Gly 340 345 350 Phe Val Ser Arg Ile Leu ProLys Ile Tyr Pro Ile Ser Ile Ile Arg 355 360 365 Ala Asp Pro Asp Thr GlyGlu Pro Ile Arg Asp Arg Asn Gly Leu Cys 370 375 380 Gln Leu Cys Ala ProAsn Glu Pro Gly Val Phe Ile Gly Lys Ile Val 385 390 395 400 Lys Gly AsnPro Ser Arg Glu Phe Leu Gly Tyr Val Asp Glu Lys Ala 405 410 415 Ser AlaLys Lys Ile Val Lys Asp Val Phe Lys His Gly Asp Met Ala 420 425 430 PheIle Ser Gly Asp Leu Leu Val Ala Asp Glu Lys Gly Tyr Leu Tyr 435 440 445Phe Lys Asp Arg Thr Gly Asp Thr Phe Arg Trp Lys Gly Glu Asn Val 450 455460 Ser Thr Ser Glu Val Glu Ala Gln Val Ser Asn Val Ala Gly Tyr Lys 465470 475 480 Asp Thr Val Val Tyr Gly Val Thr Ile Pro His Thr Glu Gly ArgAla 485 490 495 Gly Met Ala Ala Ile Tyr Asp Pro Glu Arg Glu Leu Asp LeuAsp Val 500 505 510 Phe Ala Ala Ser Leu Ala Lys Val Leu Pro Ala Tyr AlaArg Pro Gln 515 520 525 Ile Ile Arg Leu Leu Thr Lys Val Asp Leu Thr GlyThr Phe Lys Leu 530 535 540 Arg Lys Val Asp Leu Gln Lys Glu Gly Tyr AspPro Asn Ala Ile Lys 545 550 555 560 Asp Ala Leu Tyr Tyr Gln Thr Ser LysGly Arg Tyr Glu Leu Leu Thr 565 570 575 Pro Gln Val Tyr Asp Gln Val GlnArg Asn Glu Ile Arg Phe 580 585 590 <210> SEQ ID NO 76 <211> LENGTH: 173<212> TYPE: DNA <213> ORGANISM: Danio rerio <400> SEQUENCE: 76agtgtagata ccacaggaac gtttaaaatc cagaagacca gactgcaaag ggaaggatac 60gatccacggc tcacaactga ccagatctac ttcctaaact ccagagcagg gcgttacgag 120cttgtcaacg aggagctgta caatgcattt gaacaagggc aggatttccc ttt 173 <210> SEQID NO 77 <211> LENGTH: 57 <212> TYPE: PRT <213> ORGANISM: Danio rerio<400> SEQUENCE: 77 Ser Val Asp Thr Thr Gly Thr Phe Lys Ile Gln Lys ThrArg Leu Gln 1 5 10 15 Arg Glu Gly Tyr Asp Pro Arg Leu Thr Thr Asp GlnIle Tyr Phe Leu 20 25 30 Asn Ser Arg Ala Gly Arg Tyr Glu Leu Val Asn GluGlu Leu Tyr Asn 35 40 45 Ala Phe Glu Gln Gly Gln Asp Phe Pro 50 55 <210>SEQ ID NO 78 <211> LENGTH: 1953 <212> TYPE: DNA <213> ORGANISM:Caenorhabditis elegans <400> SEQUENCE: 78 atgaagctgg aggagcttgtgacagttatg cttctcacag tggctgtcat tgctcagaat 60 cttccgattg gagtaatattggctggagtt cttattttat acatcacagt ggttcatgga 120 gatttcattt atagaagttatcttacgttg aatagggatt taacaggatt ggctctaatt 180 attgaagtca aaatcgacctatggtggagg ttgcatcaga ataaaggaat ccatgaactg 240 tttttggata ttgtgaaaaagaatccaaat aagccggcga tgattgacat cgagacgaat 300 acaacagaaa catacgcagagttcaatgca cattgtaata gatatgccaa ttatttccag 360 ggtcttggct atcgatccggagacgttgtc gccttgtaca tggagaactc ggtcgagttt 420 gtggccgcgt ggatgggactcgcaaaaatc ggagttgtaa cggcttggat caactcgaat 480 ttgaaaagag agcaacttgttcattgtatc actgcgagca agacaaaggc gattatcaca 540 agtgtaacac ttcagaatattatgcttgat gctatcgatc agaagctgtt tgatgttgag 600 ggaattgagg tttactctgtcggagagccc aagaagaatt ctggattcaa gaatctcaag 660 aagaagttgg atgctcaaattactacggaa ccaaagaccc ttgacatagt agattttaaa 720 agtattcttt gcttcatctatacaagtggt actactggaa tgccaaaagc cgctgtcatg 780 aagcacttca gatattactcgattgccgtt ggagccgcaa aatcattcgg aatccgccct 840 tctgatcgta tgtacgtctcgatgccaatt tatcacactg cagctggaat tcttggagtt 900 gggcaagctc tgttgggtggatcatcgtgt gtcattagaa aaaaattctc ggctagcaac 960 ttttggaggg attgtgtaaagtatgattgt acagtttcac aatacattgg agagatttgt 1020 cggtacttgt tggctcagccagttgtggaa gaggaatcca ggcatagaat gagattgttg 1080 gttggaaacg gactccgtgctgaaatctgg caaccatttg tagatcgatt ccgtgtcaga 1140 attggagaac tttatggttcaactgaagga acttcatctc tcgtgaacat tgacggacat 1200 gtcggagctt gcggattcttgccaatatcc ccattaacaa agaaaatgca tccggttcga 1260 ttaattaagg ttgatgatgtcactggagaa gcaatccgaa cttccgatgg actttgcatt 1320 gcatgtaatc caggagagtctggagcaatg gtgtcgacga tcagaaaaaa taatccatta 1380 ttgcaattcg agggatatctgaataagaag gaaacgaata aaaagattat cagagatgtc 1440 ttcgcaaagg gagatagttgctttttgact ggagatcttc ttcattggga tcgtcttggt 1500 tatgtatatt tcaaggatcgtactggagat actttccgtt ggaagggaga gaatgtgtcg 1560 actactgaag tcgaggcaattcttcatcca attactggat tgtctgatgc aactgtttat 1620 ggtgtagagg ttcctcaaagagagggaaga gttggaatgg cgtcagttgt tcgagttgta 1680 tcgcatgagg aagatgaaactcaatttgtt catagagttg gagcaagact tgcctcttcg 1740 cttaccagct acgcgattcctcagtttatg cgaatttgtc aggatgttga gaaaacaggt 1800 acattcaaac ttgtgaagacgaatctacaa cgattaggta tcatggatgc tccttcagat 1860 tcaatttaca tctacaattctgaaaatcgc aattttgtgc cgttcgacaa tgatttgagg 1920 tgcaaggtct cactgggaagttatccattt taa 1953 <210> SEQ ID NO 79 <211> LENGTH: 650 <212> TYPE: PRT<213> ORGANISM: Caenorhabditis elegans <400> SEQUENCE: 79 Met Lys LeuGlu Glu Leu Val Thr Val Met Leu Leu Thr Val Ala Val 1 5 10 15 Ile AlaGln Asn Leu Pro Ile Gly Val Ile Leu Ala Gly Val Leu Ile 20 25 30 Leu TyrIle Thr Val Val His Gly Asp Phe Ile Tyr Arg Ser Tyr Leu 35 40 45 Thr LeuAsn Arg Asp Leu Thr Gly Leu Ala Leu Ile Ile Glu Val Lys 50 55 60 Ile AspLeu Trp Trp Arg Leu His Gln Asn Lys Gly Ile His Glu Leu 65 70 75 80 PheLeu Asp Ile Val Lys Lys Asn Pro Asn Lys Pro Ala Met Ile Asp 85 90 95 IleGlu Thr Asn Thr Thr Glu Thr Tyr Ala Glu Phe Asn Ala His Cys 100 105 110Asn Arg Tyr Ala Asn Tyr Phe Gln Gly Leu Gly Tyr Arg Ser Gly Asp 115 120125 Val Val Ala Leu Tyr Met Glu Asn Ser Val Glu Phe Val Ala Ala Trp 130135 140 Met Gly Leu Ala Lys Ile Gly Val Val Thr Ala Trp Ile Asn Ser Asn145 150 155 160 Leu Lys Arg Glu Gln Leu Val His Cys Ile Thr Ala Ser LysThr Lys 165 170 175 Ala Ile Ile Thr Ser Val Thr Leu Gln Asn Ile Met LeuAsp Ala Ile 180 185 190 Asp Gln Lys Leu Phe Asp Val Glu Gly Ile Glu ValTyr Ser Val Gly 195 200 205 Glu Pro Lys Lys Asn Ser Gly Phe Lys Asn LeuLys Lys Lys Leu Asp 210 215 220 Ala Gln Ile Thr Thr Glu Pro Lys Thr LeuAsp Ile Val Asp Phe Lys 225 230 235 240 Ser Ile Leu Cys Phe Ile Tyr ThrSer Gly Thr Thr Gly Met Pro Lys 245 250 255 Ala Ala Val Met Lys His PheArg Tyr Tyr Ser Ile Ala Val Gly Ala 260 265 270 Ala Lys Ser Phe Gly IleArg Pro Ser Asp Arg Met Tyr Val Ser Met 275 280 285 Pro Ile Tyr His ThrAla Ala Gly Ile Leu Gly Val Gly Gln Ala Leu 290 295 300 Leu Gly Gly SerSer Cys Val Ile Arg Lys Lys Phe Ser Ala Ser Asn 305 310 315 320 Phe TrpArg Asp Cys Val Lys Tyr Asp Cys Thr Val Ser Gln Tyr Ile 325 330 335 GlyGlu Ile Cys Arg Tyr Leu Leu Ala Gln Pro Val Val Glu Glu Glu 340 345 350Ser Arg His Arg Met Arg Leu Leu Val Gly Asn Gly Leu Arg Ala Glu 355 360365 Ile Trp Gln Pro Phe Val Asp Arg Phe Arg Val Arg Ile Gly Glu Leu 370375 380 Tyr Gly Ser Thr Glu Gly Thr Ser Ser Leu Val Asn Ile Asp Gly His385 390 395 400 Val Gly Ala Cys Gly Phe Leu Pro Ile Ser Pro Leu Thr LysLys Met 405 410 415 His Pro Val Arg Leu Ile Lys Val Asp Asp Val Thr GlyGlu Ala Ile 420 425 430 Arg Thr Ser Asp Gly Leu Cys Ile Ala Cys Asn ProGly Glu Ser Gly 435 440 445 Ala Met Val Ser Thr Ile Arg Lys Asn Asn ProLeu Leu Gln Phe Glu 450 455 460 Gly Tyr Leu Asn Lys Lys Glu Thr Asn LysLys Ile Ile Arg Asp Val 465 470 475 480 Phe Ala Lys Gly Asp Ser Cys PheLeu Thr Gly Asp Leu Leu His Trp 485 490 495 Asp Arg Leu Gly Tyr Val TyrPhe Lys Asp Arg Thr Gly Asp Thr Phe 500 505 510 Arg Trp Lys Gly Glu AsnVal Ser Thr Thr Glu Val Glu Ala Ile Leu 515 520 525 His Pro Ile Thr GlyLeu Ser Asp Ala Thr Val Tyr Gly Val Glu Val 530 535 540 Pro Gln Arg GluGly Arg Val Gly Met Ala Ser Val Val Arg Val Val 545 550 555 560 Ser HisGlu Glu Asp Glu Thr Gln Phe Val His Arg Val Gly Ala Arg 565 570 575 LeuAla Ser Ser Leu Thr Ser Tyr Ala Ile Pro Gln Phe Met Arg Ile 580 585 590Cys Gln Asp Val Glu Lys Thr Gly Thr Phe Lys Leu Val Lys Thr Asn 595 600605 Leu Gln Arg Leu Gly Ile Met Asp Ala Pro Ser Asp Ser Ile Tyr Ile 610615 620 Tyr Asn Ser Glu Asn Arg Asn Phe Val Pro Phe Asp Asn Asp Leu Arg625 630 635 640 Cys Lys Val Ser Leu Gly Ser Tyr Pro Phe 645 650 <210>SEQ ID NO 80 <211> LENGTH: 1968 <212> TYPE: DNA <213> ORGANISM:Caenorhabditis elegans <400> SEQUENCE: 80 atgagggaaa tgccggacagtcccaagttt gcgttagtca cgtttgttgt gtatgcagtg 60 gttttgtaca atgtcaacagcgttttctgg aaatttgtat tcatcggata tgttgtattt 120 aggctgcttc gcactgattttggaagaaga gcacttgcca cgttacctag agattttgcg 180 ggactgaagc tcttaatatcggttaagtcg acaattcgtg gcttgttcaa gaaagatcgc 240 ccaattcatg aaatctttttgaatcaggtg aaacagcatc caaacaaagt ggcgattatt 300 gaaattgaaa gtggtaggcagttgacgtat caagaattga atgcgttagc taatcagtat 360 gctaaccttt acgtgagtgaaggttacaaa atgggcgacg ttgtcgcttt gtttatggaa 420 aatagcatcg acttctttgcaatttggctg ggactttcca agattggagt cgtgtcggcg 480 ttcatcaact caaacttgaagttggagcca ttggcacatt cgattaatgt ttcgaagtgc 540 aaatcatgca ttaccaatatcaatctgttg ccgatgttca aagccgctcg tgaaaagaat 600 ctgatcagtg acgagatccacgtgtttctg gctggaactc aggttgatgg acgtcataga 660 agtcttcagc aagatctccatcttttctct gaggatgaac ctccagttat agacggactc 720 aattttagaa gcgttctgtgttatatttac acttccggta ctaccggaaa tccaaagcca 780 gccgtcatta aacacttccgttacttctgg attgcgatgg gagcaggaaa agcatttgga 840 attaataagt cagacgttgtgtacattacg atgccaatgt atcactctgc cgccggtatc 900 atgggtattg gatcattaattgcattcggg tcgaccgctg ttattaggaa aaagttttcg 960 gcaagcaact tctggaaagattgcgtcaag tacaacgtca cagcgacaca gtacattgga 1020 gaaatctgca ggtatcttctggcagcgaat ccatgtcctg aagagaaaca acacaacgtg 1080 cgattgatgt ggggaaatggtttgagagga caaatttgga aagagtttgt aggaagattt 1140 ggaattaaga aaattggagagttgtacggc tcaacagaag gaaactccaa tattgttaac 1200 gtggataacc atgttggagcttgtggattc atgccaattt atccccatat tggatccctc 1260 tacccagttc gacttattaaggttgataga gccactggag agcttgaacg tgataagaac 1320 ggactctgtg tgccgtgtgtgcctggtgaa actggggaaa tggttggcgt tatcaaggag 1380 aaagatattc ttctaaagttcgaaggatat gtcagcgaag gggatactgc aaagaaaatc 1440 tacagagatg tgttcaagcatggagataag gtgtttgcaa gtggagatat tcttcattgg 1500 gatgatcttg gatacttgtactttgtggac cgttgtggag acactttccg ttggaaaggg 1560 gagaacgtgt caactactgaagttgaggga attcttcagc ctgtgatgga tgtggaagat 1620 gcaactgttt atggagtcactgtcggtaaa atggaggggc gtgccggaat ggctggtatt 1680 gtcgtcaagg atggaacggatgttgagaaa ttcatcgccg atattacttc tcgactgacc 1740 gaaaatctgg cgtcttacgcaatccctgtt ttcattcggc tgtgcaagga agttgatcga 1800 accggaacct tcaaactcaagaagactgat cttcaaaaac aaggttacga cctggttgct 1860 tgtaaaggag acccaatttactactggtca gctgcagaaa aatcctacaa accactgact 1920 gacaaaatgc aacaggatattgacactggt gtttatgatc gcatttaa 1968 <210> SEQ ID NO 81 <211> LENGTH: 655<212> TYPE: PRT <213> ORGANISM: Caenorhabditis elegans <400> SEQUENCE:81 Met Arg Glu Met Pro Asp Ser Pro Lys Phe Ala Leu Val Thr Phe Val 1 510 15 Val Tyr Ala Val Val Leu Tyr Asn Val Asn Ser Val Phe Trp Lys Phe 2025 30 Val Phe Ile Gly Tyr Val Val Phe Arg Leu Leu Arg Thr Asp Phe Gly 3540 45 Arg Arg Ala Leu Ala Thr Leu Pro Arg Asp Phe Ala Gly Leu Lys Leu 5055 60 Leu Ile Ser Val Lys Ser Thr Ile Arg Gly Leu Phe Lys Lys Asp Arg 6570 75 80 Pro Ile His Glu Ile Phe Leu Asn Gln Val Lys Gln His Pro Asn Lys85 90 95 Val Ala Ile Ile Glu Ile Glu Ser Gly Arg Gln Leu Thr Tyr Gln Glu100 105 110 Leu Asn Ala Leu Ala Asn Gln Tyr Ala Asn Leu Tyr Val Ser GluGly 115 120 125 Tyr Lys Met Gly Asp Val Val Ala Leu Phe Met Glu Asn SerIle Asp 130 135 140 Phe Phe Ala Ile Trp Leu Gly Leu Ser Lys Ile Gly ValVal Ser Ala 145 150 155 160 Phe Ile Asn Ser Asn Leu Lys Leu Glu Pro LeuAla His Ser Ile Asn 165 170 175 Val Ser Lys Cys Lys Ser Cys Ile Thr AsnIle Asn Leu Leu Pro Met 180 185 190 Phe Lys Ala Ala Arg Glu Lys Asn LeuIle Ser Asp Glu Ile His Val 195 200 205 Phe Leu Ala Gly Thr Gln Val AspGly Arg His Arg Ser Leu Gln Gln 210 215 220 Asp Leu His Leu Phe Ser GluAsp Glu Pro Pro Val Ile Asp Gly Leu 225 230 235 240 Asn Phe Arg Ser ValLeu Cys Tyr Ile Tyr Thr Ser Gly Thr Thr Gly 245 250 255 Asn Pro Lys ProAla Val Ile Lys His Phe Arg Tyr Phe Trp Ile Ala 260 265 270 Met Gly AlaGly Lys Ala Phe Gly Ile Asn Lys Ser Asp Val Val Tyr 275 280 285 Ile ThrMet Pro Met Tyr His Ser Ala Ala Gly Ile Met Gly Ile Gly 290 295 300 SerLeu Ile Ala Phe Gly Ser Thr Ala Val Ile Arg Lys Lys Phe Ser 305 310 315320 Ala Ser Asn Phe Trp Lys Asp Cys Val Lys Tyr Asn Val Thr Ala Thr 325330 335 Gln Tyr Ile Gly Glu Ile Cys Arg Tyr Leu Leu Ala Ala Asn Pro Cys340 345 350 Pro Glu Glu Lys Gln His Asn Val Arg Leu Met Trp Gly Asn GlyLeu 355 360 365 Arg Gly Gln Ile Trp Lys Glu Phe Val Gly Arg Phe Gly IleLys Lys 370 375 380 Ile Gly Glu Leu Tyr Gly Ser Thr Glu Gly Asn Ser AsnIle Val Asn 385 390 395 400 Val Asp Asn His Val Gly Ala Cys Gly Phe MetPro Ile Tyr Pro His 405 410 415 Ile Gly Ser Leu Tyr Pro Val Arg Leu IleLys Val Asp Arg Ala Thr 420 425 430 Gly Glu Leu Glu Arg Asp Lys Asn GlyLeu Cys Val Pro Cys Val Pro 435 440 445 Gly Glu Thr Gly Glu Met Val GlyVal Ile Lys Glu Lys Asp Ile Leu 450 455 460 Leu Lys Phe Glu Gly Tyr ValSer Glu Gly Asp Thr Ala Lys Lys Ile 465 470 475 480 Tyr Arg Asp Val PheLys His Gly Asp Lys Val Phe Ala Ser Gly Asp 485 490 495 Ile Leu His TrpAsp Asp Leu Gly Tyr Leu Tyr Phe Val Asp Arg Cys 500 505 510 Gly Asp ThrPhe Arg Trp Lys Gly Glu Asn Val Ser Thr Thr Glu Val 515 520 525 Glu GlyIle Leu Gln Pro Val Met Asp Val Glu Asp Ala Thr Val Tyr 530 535 540 GlyVal Thr Val Gly Lys Met Glu Gly Arg Ala Gly Met Ala Gly Ile 545 550 555560 Val Val Lys Asp Gly Thr Asp Val Glu Lys Phe Ile Ala Asp Ile Thr 565570 575 Ser Arg Leu Thr Glu Asn Leu Ala Ser Tyr Ala Ile Pro Val Phe Ile580 585 590 Arg Leu Cys Lys Glu Val Asp Arg Thr Gly Thr Phe Lys Leu LysLys 595 600 605 Thr Asp Leu Gln Lys Gln Gly Tyr Asp Leu Val Ala Cys LysGly Asp 610 615 620 Pro Ile Tyr Tyr Trp Ser Ala Ala Glu Lys Ser Tyr LysPro Leu Thr 625 630 635 640 Asp Lys Met Gln Gln Asp Ile Asp Thr Gly ValTyr Asp Arg Ile 645 650 655 <210> SEQ ID NO 82 <211> LENGTH: 1932 <212>TYPE: DNA <213> ORGANISM: Cochliobolus heterostrophus <400> SEQUENCE: 82atggcgtgta tgcatcaggc tcagctatac aatgatctag aggaattgct aactggtcca 60tcagtaccca tcgttgctgg agctgctgga gctgcagctc tcactgccta cattaacgcc 120aaataccaca tagcccatga tctcaagacc ctcggtggtg gattgacaca atcgtccgaa 180gcgattgatt tcataaaccg ccgcgtcgca caaaagcgcg tcctcacgca ccacatcttc 240caggagcagg tccaaaaaca atcaaatcat ccctttctta tctttgaggg caagacatgg 300tcttacaagg agttctctga ggcatacacg agggtcgcga actggctgat tgatgagctg 360gacgtacaag taggggagat ggtcgcaatt gatggcggaa atagtgcaga gcacctgatg 420ctttggcttg cacttgatgc aatcggtgcg gctacgagtt ttttgaactg gaacctgaca 480ggggcagggt taattcattg cataaagcta tgcgaatgtc gattcgttat cgcagacatc 540gatattaaag cgaacattga accgtgccgt ggcgaactgg aggagacggg catcaacatt 600cactactatg acccatcctt catctcatcg ctaccgaata acacgccaat tcccgacagc 660cgcactgaga acattgaatt agattcagta cgaggactga tatacacatc tggaaccact 720ggtctaccta aaggcgtgtt tataagcact ggccgcgagc ttaggactga ctggtcgatt 780tcaaagtatc taaatctcaa gcccacggat cgaatgtata catgtatgcc gctctaccat 840gccgctgcac acagcctctg tacagcatca gttattcatg gtggaggtac cgtggtattg 900agcaggaaat tctcacacaa gaagttctgg cctgaagttg tggcttcgga agcaaatatc 960attcagtacg ttggtgaatt aggtcgatat ctcctgaatg gtccaaagag tccttacgac 1020agggcccata aagtccagat ggcgtggggc aatggcatgc gtccagacgt gtgggaagcg 1080tttcgtgaac gcttcaacat accaattatt catgagctct atgccgcaac cgatgggctc 1140gggtcaatga ccaatcgtaa cgcgggccct tttacagcaa actgtattgc gctgcgaggg 1200ctgatctggc actggaaatt tcgaaatcag gaagtgctgg tcaagatgga tctcgatact 1260gatgagatca tgagagatcg caatgggttt gcgatacgat gcgctgtcaa tgaacctgga 1320cagatgcttt ttcggctgac acccgaaact ctggctggtg caccaagcta ctacaacaac 1380gaaacggcca cacagagcag gcggattaca gatgtgtttc aaaagggtga cctgtggttc 1440aagtccggtg acatgctacg gcaagacgcc gaaggccgcg tctactttgt cgatcgacta 1500ggcgatacgt tccgctggaa atccgaaaac gtttctacca atgaagtcgc ggacgtgatg 1560ggcacatttc ctcagattgc tgaaacgaat gtatacggtg tccttgtgcc gggtaacgat 1620ggtcgagtgc gcagcctcaa ttgtcatggc agacggcgtg acagagtcga cattcgcttc 1680gctgcccttg caaagcacgc ccgagatcgg ttaccgggtt atgctgtacc actgtttctg 1740agggtaactc cagcacttga atatacgggc acattaaaga ttcagaaagg acgcctcaag 1800caggaaggta tagacccaga taagatttcc ggcgaagata agttatactg gctgccgcct 1860ggtagcgata tatatttacc atttggaaag atggagtggc agggaattgt agataagcgt 1920atacggctgt ga 1932 <210> SEQ ID NO 83 <211> LENGTH: 643 <212> TYPE: PRT<213> ORGANISM: Cochliobolus heterostrophus <400> SEQUENCE: 83 Met AlaCys Met His Gln Ala Gln Leu Tyr Asn Asp Leu Glu Glu Leu 1 5 10 15 LeuThr Gly Pro Ser Val Pro Ile Val Ala Gly Ala Ala Gly Ala Ala 20 25 30 AlaLeu Thr Ala Tyr Ile Asn Ala Lys Tyr His Ile Ala His Asp Leu 35 40 45 LysThr Leu Gly Gly Gly Leu Thr Gln Ser Ser Glu Ala Ile Asp Phe 50 55 60 IleAsn Arg Arg Val Ala Gln Lys Arg Val Leu Thr His His Ile Phe 65 70 75 80Gln Glu Gln Val Gln Lys Gln Ser Asn His Pro Phe Leu Ile Phe Glu 85 90 95Gly Lys Thr Trp Ser Tyr Lys Glu Phe Ser Glu Ala Tyr Thr Arg Val 100 105110 Ala Asn Trp Leu Ile Asp Glu Leu Asp Val Gln Val Gly Glu Met Val 115120 125 Ala Ile Asp Gly Gly Asn Ser Ala Glu His Leu Met Leu Trp Leu Ala130 135 140 Leu Asp Ala Ile Gly Ala Ala Thr Ser Phe Leu Asn Trp Asn LeuThr 145 150 155 160 Gly Ala Gly Leu Ile His Cys Ile Lys Leu Cys Glu CysArg Phe Val 165 170 175 Ile Ala Asp Ile Asp Ile Lys Ala Asn Ile Glu ProCys Arg Gly Glu 180 185 190 Leu Glu Glu Thr Gly Ile Asn Ile His Tyr TyrAsp Pro Ser Phe Ile 195 200 205 Ser Ser Leu Pro Asn Asn Thr Pro Ile ProAsp Ser Arg Thr Glu Asn 210 215 220 Ile Glu Leu Asp Ser Val Arg Gly LeuIle Tyr Thr Ser Gly Thr Thr 225 230 235 240 Gly Leu Pro Lys Gly Val PheIle Ser Thr Gly Arg Glu Leu Arg Thr 245 250 255 Asp Trp Ser Ile Ser LysTyr Leu Asn Leu Lys Pro Thr Asp Arg Met 260 265 270 Tyr Thr Cys Met ProLeu Tyr His Ala Ala Ala His Ser Leu Cys Thr 275 280 285 Ala Ser Val IleHis Gly Gly Gly Thr Val Val Leu Ser Arg Lys Phe 290 295 300 Ser His LysLys Phe Trp Pro Glu Val Val Ala Ser Glu Ala Asn Ile 305 310 315 320 IleGln Tyr Val Gly Glu Leu Gly Arg Tyr Leu Leu Asn Gly Pro Lys 325 330 335Ser Pro Tyr Asp Arg Ala His Lys Val Gln Met Ala Trp Gly Asn Gly 340 345350 Met Arg Pro Asp Val Trp Glu Ala Phe Arg Glu Arg Phe Asn Ile Pro 355360 365 Ile Ile His Glu Leu Tyr Ala Ala Thr Asp Gly Leu Gly Ser Met Thr370 375 380 Asn Arg Asn Ala Gly Pro Phe Thr Ala Asn Cys Ile Ala Leu ArgGly 385 390 395 400 Leu Ile Trp His Trp Lys Phe Arg Asn Gln Glu Val LeuVal Lys Met 405 410 415 Asp Leu Asp Thr Asp Glu Ile Met Arg Asp Arg AsnGly Phe Ala Ile 420 425 430 Arg Cys Ala Val Asn Glu Pro Gly Gln Met LeuPhe Arg Leu Thr Pro 435 440 445 Glu Thr Leu Ala Gly Ala Pro Ser Tyr TyrAsn Asn Glu Thr Ala Thr 450 455 460 Gln Ser Arg Arg Ile Thr Asp Val PheGln Lys Gly Asp Leu Trp Phe 465 470 475 480 Lys Ser Gly Asp Met Leu ArgGln Asp Ala Glu Gly Arg Val Tyr Phe 485 490 495 Val Asp Arg Leu Gly AspThr Phe Arg Trp Lys Ser Glu Asn Val Ser 500 505 510 Thr Asn Glu Val AlaAsp Val Met Gly Thr Phe Pro Gln Ile Ala Glu 515 520 525 Thr Asn Val TyrGly Val Leu Val Pro Gly Asn Asp Gly Arg Val Arg 530 535 540 Ser Leu AsnCys His Gly Arg Arg Arg Asp Arg Val Asp Ile Arg Phe 545 550 555 560 AlaAla Leu Ala Lys His Ala Arg Asp Arg Leu Pro Gly Tyr Ala Val 565 570 575Pro Leu Phe Leu Arg Val Thr Pro Ala Leu Glu Tyr Thr Gly Thr Leu 580 585590 Lys Ile Gln Lys Gly Arg Leu Lys Gln Glu Gly Ile Asp Pro Asp Lys 595600 605 Ile Ser Gly Glu Asp Lys Leu Tyr Trp Leu Pro Pro Gly Ser Asp Ile610 615 620 Tyr Leu Pro Phe Gly Lys Met Glu Trp Gln Gly Ile Val Asp LysArg 625 630 635 640 Ile Arg Leu <210> SEQ ID NO 84 <211> LENGTH: 597<212> TYPE: DNA <213> ORGANISM: Aspergillus nidulans <400> SEQUENCE: 84ctttaccatt catcagcttc attctgcatt tttagcttga cggcagccgg gtctacgctg 60atcatcggcc gcaagttctc cgcgagaaac ttcataaagg aagcgcgcga gaacgacgcc 120acggtcatcc agtacgtggg tgagaccttg cgatatctgc tcgccacccc cggtgaaacc 180gatccagtta ctggcgaaga cctggacaaa aagcacaata ttcgagcagt atacggcaac 240gggctacggc cggatatctg gaaccgcttc aaggagcgct tcaacgtgcc gacggttgcc 300gaattttatg ctgcaaccga gagcccaggc ggaacatgga actattcaac aaatgacttc 360actgccggag ccattgggca cactggcgtg cttagtggat ggcttcttgg acgcggcctt 420actattgtcg aggtggacca ggaatcacag gaaccatggc gcgatcccca aaccgggttc 480tgcaagccgg tcccgcgagg cgaagcaggc gagctcctgt atgccattga tccggccgac 540ccgggcgaga ccttccaggg ctactaccgc aactccttta gagcacactg gcggccg 597 <210>SEQ ID NO 85 <211> LENGTH: 199 <212> TYPE: PRT <213> ORGANISM:Aspergillus nidulans <400> SEQUENCE: 85 Leu Tyr His Ser Ser Ala Ser PheCys Ile Phe Ser Leu Thr Ala Ala 1 5 10 15 Gly Ser Thr Leu Ile Ile GlyArg Lys Phe Ser Ala Arg Asn Phe Ile 20 25 30 Lys Glu Ala Arg Glu Asn AspAla Thr Val Ile Gln Tyr Val Gly Glu 35 40 45 Thr Leu Arg Tyr Leu Leu AlaThr Pro Gly Glu Thr Asp Pro Val Thr 50 55 60 Gly Glu Asp Leu Asp Lys LysHis Asn Ile Arg Ala Val Tyr Gly Asn 65 70 75 80 Gly Leu Arg Pro Asp IleTrp Asn Arg Phe Lys Glu Arg Phe Asn Val 85 90 95 Pro Thr Val Ala Glu PheTyr Ala Ala Thr Glu Ser Pro Gly Gly Thr 100 105 110 Trp Asn Tyr Ser ThrAsn Asp Phe Thr Ala Gly Ala Ile Gly His Thr 115 120 125 Gly Val Leu SerGly Trp Leu Leu Gly Arg Gly Leu Thr Ile Val Glu 130 135 140 Val Asp GlnGlu Ser Gln Glu Pro Trp Arg Asp Pro Gln Thr Gly Phe 145 150 155 160 CysLys Pro Val Pro Arg Gly Glu Ala Gly Glu Leu Leu Tyr Ala Ile 165 170 175Asp Pro Ala Asp Pro Gly Glu Thr Phe Gln Gly Tyr Tyr Arg Asn Ser 180 185190 Phe Arg Ala His Trp Arg Pro 195 <210> SEQ ID NO 86 <211> LENGTH: 522<212> TYPE: DNA <213> ORGANISM: Magnaporthe grisea <220> FEATURE: <221>NAME/KEY: misc_feature <222> LOCATION: (1)...(522) <223> OTHERINFORMATION: n = A,T,C or G <220> FEATURE: <221> NAME/KEY: misc_feature<222> LOCATION: 111 <223> OTHER INFORMATION: n = A,T,C or G <400>SEQUENCE: 86 gcaaaggccg acgcgtggct gcggacgggt aacgtgatca gggcggacaacgaagggcga 60 ctcttcttcc acgaccggat cggagacacg ttccgatgga agggagagacngtcagcaca 120 caagaggtca gtttggtgct cggacgacac gactcaatca aggaggccaacgtgtacggc 180 gtgacggtgc cgaaccacga cgggcgggcc ggctgcgctg cgctcacgctatcagacgct 240 ctggcgactg aaaagaagct gggcgatgag ctgctaaagg gattggctactcactcgtcg 300 acttcgcttc ccaagtttgc ggtgccgcag ttcctacggg tggtgcgcggcgagatgcag 360 tcaacgggca ccaacaagca acagaagcac gacctgaggg tgcagggtgtagagccgggc 420 aaggtgggcg tagacgaggt gtactggttg cggggaggga catatgtaccattcggaaca 480 gaggattggg atgggttgaa gaagggtctt gtgaagttgt ga 522 <210>SEQ ID NO 87 <211> LENGTH: 173 <212> TYPE: PRT <213> ORGANISM:Magnaporthe grisea <400> SEQUENCE: 87 Ala Lys Ala Asp Ala Trp Leu ArgThr Gly Asn Val Ile Arg Ala Asp 1 5 10 15 Asn Glu Gly Arg Leu Phe PheHis Asp Arg Ile Gly Asp Thr Phe Arg 20 25 30 Trp Lys Gly Glu Thr Val SerThr Gln Glu Val Ser Leu Val Leu Gly 35 40 45 Arg His Asp Ser Ile Lys GluAla Asn Val Tyr Gly Val Thr Val Pro 50 55 60 Asn His Asp Gly Arg Ala GlyCys Ala Ala Leu Thr Leu Ser Asp Ala 65 70 75 80 Leu Ala Thr Glu Lys LysLeu Gly Asp Glu Leu Leu Lys Gly Leu Ala 85 90 95 Thr His Ser Ser Thr SerLeu Pro Lys Phe Ala Val Pro Gln Phe Leu 100 105 110 Arg Val Val Arg GlyGlu Met Gln Ser Thr Gly Thr Asn Lys Gln Gln 115 120 125 Lys His Asp LeuArg Val Gln Gly Val Glu Pro Gly Lys Val Gly Val 130 135 140 Asp Glu ValTyr Trp Leu Arg Gly Gly Thr Tyr Val Pro Phe Gly Thr 145 150 155 160 GluAsp Trp Asp Gly Leu Lys Lys Gly Leu Val Lys Leu 165 170 <210> SEQ ID NO88 <211> LENGTH: 1872 <212> TYPE: DNA <213> ORGANISM: Saccharomycescerevisiae <400> SEQUENCE: 88 atgtctccca tacaggttgt tgtctttgccttgtcaagga ttttcctgct attattcaga 60 cttatcaagc taattataac ccctatccagaaatcactgg gttatctatt tggtaattat 120 tttgatgaat tagaccgtaa atatagatacaaggaggatt ggtatattat tccttacttt 180 ttgaaaagcg tgttttgtta tatcattgatgtgagaagac ataggtttca aaactggtac 240 ttatttatta aacaggtcca acaaaatggtgaccatttag cgattagtta cacccgtccc 300 atggccgaaa agggagaatt tcaactcgaaacctttacgt atattgaaac ttataacata 360 gtgttgagat tgtctcatat tttgcattttgattataacg ttcaggccgg tgactacgtg 420 gcaatcgatt gtactaataa acctcttttcgtatttttat ggctttcttt gtggaacatt 480 ggggctattc cagctttttt aaactataatactaaaggca ctccgctggt tcactcccta 540 aagatttcca atattacgca ggtatttattgaccctgatg ccagtaatcc gatcagagaa 600 tcggaagaag aaatcaaaaa cgcacttcctgatgttaaat taaactatct tgaagaacaa 660 gacttaatgc atgaactttt aaattcgcaatcaccggaat tcttacaaca agacaacgtt 720 aggacaccac taggcttgac cgattttaaaccctctatgt taatttatac atctggaacc 780 actggtttgc ctaaatccgc tattatgtcttggagaaaat cctccgtagg ttgtcaagtt 840 tttggtcatg ttttacatat gactaatgaaagcactgtgt tcacagccat gccattgttc 900 cattcaactg ctgccttatt aggtgcgtgcgccattctat ctcacggtgg ttgccttgcg 960 ttatcgcata aattttctgc cagtacattttggaagcaag tttatttaac aggagccacg 1020 cacatccaat atgtcggaga agtctgtagatacctgttac atacgccaat ttctaagtat 1080 gaaaagatgc ataaggtgaa ggttgcttatggtaacgggc tgagacctga catctggcag 1140 gacttcagga agaggttcaa catagaagttattggtgaat tctatgccgc aactgaagct 1200 ccttttgcta caactacctt ccagaaaggtgactttggaa ttggcgcatg taggaactat 1260 ggtactataa ttcaatggtt tttgtcattccaacaaacat tggtaaggat ggacccaaat 1320 gacgattccg ttatatatag aaattccaagggtttctgcg aagtggcccc tgttggcgaa 1380 ccaggagaaa tgttaatgag aatctttttccctaaaaaac cagaaacatc ttttcaaggt 1440 tatcttggta atgccaagga aacaaagtccaaagttgtga gggatgtctt cagacgtggc 1500 gatgcttggt atagatgtgg agatttattaaaagcggacg aatatggatt atggtatttc 1560 cttgatagaa tgggtgatac tttcagatggaaatctgaaa atgtttccac tactgaagta 1620 gaagatcagt tgacggccag taacaaagaacaatatgcac aagttctagt tgttggtatt 1680 aaagtaccta aatatgaagg tagagctggttttgcagtta ttaaactaac tgacaactct 1740 cttgacatca ctgcaaagac caaattattaaatgattcct tgagccggtt aaatctaccg 1800 tcttatgcta tgcccctatt tgttaaatttgttgatgaaa ttaaaatgac agataacctc 1860 ataaaatttt ga 1872 <210> SEQ ID NO89 <211> LENGTH: 623 <212> TYPE: PRT <213> ORGANISM: Saccharomycescerevisiae <400> SEQUENCE: 89 Met Ser Pro Ile Gln Val Val Val Phe AlaLeu Ser Arg Ile Phe Leu 1 5 10 15 Leu Leu Phe Arg Leu Ile Lys Leu IleIle Thr Pro Ile Gln Lys Ser 20 25 30 Leu Gly Tyr Leu Phe Gly Asn Tyr PheAsp Glu Leu Asp Arg Lys Tyr 35 40 45 Arg Tyr Lys Glu Asp Trp Tyr Ile IlePro Tyr Phe Leu Lys Ser Val 50 55 60 Phe Cys Tyr Ile Ile Asp Val Arg ArgHis Arg Phe Gln Asn Trp Tyr 65 70 75 80 Leu Phe Ile Lys Gln Val Gln GlnAsn Gly Asp His Leu Ala Ile Ser 85 90 95 Tyr Thr Arg Pro Met Ala Glu LysGly Glu Phe Gln Leu Glu Thr Phe 100 105 110 Thr Tyr Ile Glu Thr Tyr AsnIle Val Leu Arg Leu Ser His Ile Leu 115 120 125 His Phe Asp Tyr Asn ValGln Ala Gly Asp Tyr Val Ala Ile Asp Cys 130 135 140 Thr Asn Lys Pro LeuPhe Val Phe Leu Trp Leu Ser Leu Trp Asn Ile 145 150 155 160 Gly Ala IlePro Ala Phe Leu Asn Tyr Asn Thr Lys Gly Thr Pro Leu 165 170 175 Val HisSer Leu Lys Ile Ser Asn Ile Thr Gln Val Phe Ile Asp Pro 180 185 190 AspAla Ser Asn Pro Ile Arg Glu Ser Glu Glu Glu Ile Lys Asn Ala 195 200 205Leu Pro Asp Val Lys Leu Asn Tyr Leu Glu Glu Gln Asp Leu Met His 210 215220 Glu Leu Leu Asn Ser Gln Ser Pro Glu Phe Leu Gln Gln Asp Asn Val 225230 235 240 Arg Thr Pro Leu Gly Leu Thr Asp Phe Lys Pro Ser Met Leu IleTyr 245 250 255 Thr Ser Gly Thr Thr Gly Leu Pro Lys Ser Ala Ile Met SerTrp Arg 260 265 270 Lys Ser Ser Val Gly Cys Gln Val Phe Gly His Val LeuHis Met Thr 275 280 285 Asn Glu Ser Thr Val Phe Thr Ala Met Pro Leu PheHis Ser Thr Ala 290 295 300 Ala Leu Leu Gly Ala Cys Ala Ile Leu Ser HisGly Gly Cys Leu Ala 305 310 315 320 Leu Ser His Lys Phe Ser Ala Ser ThrPhe Trp Lys Gln Val Tyr Leu 325 330 335 Thr Gly Ala Thr His Ile Gln TyrVal Gly Glu Val Cys Arg Tyr Leu 340 345 350 Leu His Thr Pro Ile Ser LysTyr Glu Lys Met His Lys Val Lys Val 355 360 365 Ala Tyr Gly Asn Gly LeuArg Pro Asp Ile Trp Gln Asp Phe Arg Lys 370 375 380 Arg Phe Asn Ile GluVal Ile Gly Glu Phe Tyr Ala Ala Thr Glu Ala 385 390 395 400 Pro Phe AlaThr Thr Thr Phe Gln Lys Gly Asp Phe Gly Ile Gly Ala 405 410 415 Cys ArgAsn Tyr Gly Thr Ile Ile Gln Trp Phe Leu Ser Phe Gln Gln 420 425 430 ThrLeu Val Arg Met Asp Pro Asn Asp Asp Ser Val Ile Tyr Arg Asn 435 440 445Ser Lys Gly Phe Cys Glu Val Ala Pro Val Gly Glu Pro Gly Glu Met 450 455460 Leu Met Arg Ile Phe Phe Pro Lys Lys Pro Glu Thr Ser Phe Gln Gly 465470 475 480 Tyr Leu Gly Asn Ala Lys Glu Thr Lys Ser Lys Val Val Arg AspVal 485 490 495 Phe Arg Arg Gly Asp Ala Trp Tyr Arg Cys Gly Asp Leu LeuLys Ala 500 505 510 Asp Glu Tyr Gly Leu Trp Tyr Phe Leu Asp Arg Met GlyAsp Thr Phe 515 520 525 Arg Trp Lys Ser Glu Asn Val Ser Thr Thr Glu ValGlu Asp Gln Leu 530 535 540 Thr Ala Ser Asn Lys Glu Gln Tyr Ala Gln ValLeu Val Val Gly Ile 545 550 555 560 Lys Val Pro Lys Tyr Glu Gly Arg AlaGly Phe Ala Val Ile Lys Leu 565 570 575 Thr Asp Asn Ser Leu Asp Ile ThrAla Lys Thr Lys Leu Leu Asn Asp 580 585 590 Ser Leu Ser Arg Leu Asn LeuPro Ser Tyr Ala Met Pro Leu Phe Val 595 600 605 Lys Phe Val Asp Glu IleLys Met Thr Asp Asn Leu Ile Lys Phe 610 615 620 <210> SEQ ID NO 90 <211>LENGTH: 1794 <212> TYPE: DNA <213> ORGANISM: Mycobacterium tuberculosis<400> SEQUENCE: 90 gtgtccgatt actacggcgg cgcacacaca acggtcaggctgatcgacct ggcaactcgg 60 atgccgcgag tgttggcgga cacgccggtg attgtgcgtggggcaatgac cgggctgctg 120 gcccggccga attccaaggc gtcgatcggc acggtgttccaggaccgggc cgctcgctac 180 ggtgaccgag tcttcctgaa attcggcgat cagcagctgacctaccgcga cgctaacgcc 240 accgccaacc ggtacgccgc ggtgttggcc gcccgcggcgtcggccccgg cgacgtcgtt 300 ggcatcatgt tgcgtaactc acccagcaca gtcttggcgatgctggccac ggtcaagtgc 360 ggcgctatcg ccggcatgct caactaccac cagcgcggcgaggtgttggc gcacagcctg 420 ggtctgctgg acgcgaaggt actgatcgca gagtccgacttggtcagcgc cgtcgccgaa 480 tgcggcgcct cgcgcggccg ggtagcgggc gacgtgctgaccgtcgagga cgtggagcga 540 ttcgccacaa cggcgcccgc caccaacccg gcgtcggcgtcggcggtgca agccaaagac 600 accgcgttct acatcttcac ctcgggcacc accggatttcccaaggccag tgtcatgacg 660 catcatcggt ggctgcgggc gctggccgtc ttcggagggatggggctgcg gctgaagggt 720 tccgacacgc tctacagctg cctgccgctg taccacaacaacgcgttaac ggtcgcggtg 780 tcgtcggtga tcaattctgg ggcgaccctg gcgctgggtaagtcgttttc ggcgtcgcgg 840 ttctgggatg aggtgattgc caaccgggcg acggcgttcgtctacatcgg cgaaatctgc 900 cgttatctgc tcaaccagcc ggccaagccg accgaccgtgcccaccaggt gcgggtgatc 960 tgcggtaacg ggctgcggcc ggagatctgg gatgagttcaccacccgctt cggggtcgcg 1020 cgggtgtgcg agttctacgc cgccagcgaa ggcaactcggcctttatcaa catcttcaac 1080 gtgcccagga ccgccggggt atcgccgatg ccgcttgcctttgtggaata cgacctggac 1140 accggcgatc cgctgcggga tgcgagcggg cgagtgcgtcgggtacccga cggtgaaccc 1200 ggcctgttgc ttagccgggt caaccggctg cagccgttcgacggctacac cgacccggtt 1260 gccagcgaaa agaagttggt gcgcaacgct tttcgagatggcgactgttg gttcaacacc 1320 ggtgacgtga tgagcccgca gggcatgggc catgccgccttcgtcgatcg gctgggcgac 1380 accttccgct ggaagggcga gaatgtcgcc accactcaggtcgaagcggc actggcctcc 1440 gaccagaccg tcgaggagtg cacggtctac ggcgtccagattccgcgcac cggcgggcgc 1500 gccggaatgg ccgcgatcac actgcgcgct ggcgccgaattcgacggcca ggcgctggcc 1560 cgaacggttt acggtcactt gcccggctat gcacttccgctctttgttcg ggtagtgggg 1620 tcgctggcgc acaccacgac gttcaagagt cgcaaggtggagttgcgcaa ccaggcctat 1680 ggcgccgaca tcgaggatcc gctgtacgta ctggccggcccggacgaagg atatgtgccg 1740 tactacgccg aataccctga ggaggtttcg ctcggaaggcgaccgcaggg ctag 1794 <210> SEQ ID NO 91 <211> LENGTH: 597 <212> TYPE:PRT <213> ORGANISM: Mycobacterium tuberculosis <400> SEQUENCE: 91 MetSer Asp Tyr Tyr Gly Gly Ala His Thr Thr Val Arg Leu Ile Asp 1 5 10 15Leu Ala Thr Arg Met Pro Arg Val Leu Ala Asp Thr Pro Val Ile Val 20 25 30Arg Gly Ala Met Thr Gly Leu Leu Ala Arg Pro Asn Ser Lys Ala Ser 35 40 45Ile Gly Thr Val Phe Gln Asp Arg Ala Ala Arg Tyr Gly Asp Arg Val 50 55 60Phe Leu Lys Phe Gly Asp Gln Gln Leu Thr Tyr Arg Asp Ala Asn Ala 65 70 7580 Thr Ala Asn Arg Tyr Ala Ala Val Leu Ala Ala Arg Gly Val Gly Pro 85 9095 Gly Asp Val Val Gly Ile Met Leu Arg Asn Ser Pro Ser Thr Val Leu 100105 110 Ala Met Leu Ala Thr Val Lys Cys Gly Ala Ile Ala Gly Met Leu Asn115 120 125 Tyr His Gln Arg Gly Glu Val Leu Ala His Ser Leu Gly Leu LeuAsp 130 135 140 Ala Lys Val Leu Ile Ala Glu Ser Asp Leu Val Ser Ala ValAla Glu 145 150 155 160 Cys Gly Ala Ser Arg Gly Arg Val Ala Gly Asp ValLeu Thr Val Glu 165 170 175 Asp Val Glu Arg Phe Ala Thr Thr Ala Pro AlaThr Asn Pro Ala Ser 180 185 190 Ala Ser Ala Val Gln Ala Lys Asp Thr AlaPhe Tyr Ile Phe Thr Ser 195 200 205 Gly Thr Thr Gly Phe Pro Lys Ala SerVal Met Thr His His Arg Trp 210 215 220 Leu Arg Ala Leu Ala Val Phe GlyGly Met Gly Leu Arg Leu Lys Gly 225 230 235 240 Ser Asp Thr Leu Tyr SerCys Leu Pro Leu Tyr His Asn Asn Ala Leu 245 250 255 Thr Val Ala Val SerSer Val Ile Asn Ser Gly Ala Thr Leu Ala Leu 260 265 270 Gly Lys Ser PheSer Ala Ser Arg Phe Trp Asp Glu Val Ile Ala Asn 275 280 285 Arg Ala ThrAla Phe Val Tyr Ile Gly Glu Ile Cys Arg Tyr Leu Leu 290 295 300 Asn GlnPro Ala Lys Pro Thr Asp Arg Ala His Gln Val Arg Val Ile 305 310 315 320Cys Gly Asn Gly Leu Arg Pro Glu Ile Trp Asp Glu Phe Thr Thr Arg 325 330335 Phe Gly Val Ala Arg Val Cys Glu Phe Tyr Ala Ala Ser Glu Gly Asn 340345 350 Ser Ala Phe Ile Asn Ile Phe Asn Val Pro Arg Thr Ala Gly Val Ser355 360 365 Pro Met Pro Leu Ala Phe Val Glu Tyr Asp Leu Asp Thr Gly AspPro 370 375 380 Leu Arg Asp Ala Ser Gly Arg Val Arg Arg Val Pro Asp GlyGlu Pro 385 390 395 400 Gly Leu Leu Leu Ser Arg Val Asn Arg Leu Gln ProPhe Asp Gly Tyr 405 410 415 Thr Asp Pro Val Ala Ser Glu Lys Lys Leu ValArg Asn Ala Phe Arg 420 425 430 Asp Gly Asp Cys Trp Phe Asn Thr Gly AspVal Met Ser Pro Gln Gly 435 440 445 Met Gly His Ala Ala Phe Val Asp ArgLeu Gly Asp Thr Phe Arg Trp 450 455 460 Lys Gly Glu Asn Val Ala Thr ThrGln Val Glu Ala Ala Leu Ala Ser 465 470 475 480 Asp Gln Thr Val Glu GluCys Thr Val Tyr Gly Val Gln Ile Pro Arg 485 490 495 Thr Gly Gly Arg AlaGly Met Ala Ala Ile Thr Leu Arg Ala Gly Ala 500 505 510 Glu Phe Asp GlyGln Ala Leu Ala Arg Thr Val Tyr Gly His Leu Pro 515 520 525 Gly Tyr AlaLeu Pro Leu Phe Val Arg Val Val Gly Ser Leu Ala His 530 535 540 Thr ThrThr Phe Lys Ser Arg Lys Val Glu Leu Arg Asn Gln Ala Tyr 545 550 555 560Gly Ala Asp Ile Glu Asp Pro Leu Tyr Val Leu Ala Gly Pro Asp Glu 565 570575 Gly Tyr Val Pro Tyr Tyr Ala Glu Tyr Pro Glu Glu Val Ser Leu Gly 580585 590 Arg Arg Pro Gln Gly 595 <210> SEQ ID NO 92 <211> LENGTH: 646<212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 92 Met ArgAla Pro Gly Ala Gly Thr Ala Ser Val Ala Ser Leu Ala Leu 1 5 10 15 LeuTrp Phe Leu Gly Leu Pro Trp Thr Trp Ser Ala Ala Ala Ala Phe 20 25 30 CysVal Tyr Val Gly Gly Gly Gly Trp Arg Phe Leu Arg Ile Val Cys 35 40 45 LysThr Ala Arg Arg Asp Leu Phe Gly Leu Ser Val Leu Ile Arg Val 50 55 60 ArgLeu Glu Leu Arg Arg His Arg Arg Ala Gly Asp Thr Ile Pro Cys 65 70 75 80Ile Phe Gln Ala Val Ala Arg Arg Gln Pro Glu Arg Leu Ala Leu Val 85 90 95Asp Ala Ser Ser Gly Ile Cys Trp Thr Phe Ala Gln Leu Asp Thr Tyr 100 105110 Ser Asn Ala Val Ala Asn Leu Phe Arg Gln Leu Gly Phe Ala Pro Gly 115120 125 Asp Val Val Ala Val Phe Leu Glu Gly Arg Pro Glu Phe Val Gly Leu130 135 140 Trp Leu Gly Leu Ala Lys Ala Gly Val Val Ala Ala Leu Leu AsnVal 145 150 155 160 Asn Leu Arg Arg Glu Pro Leu Ala Phe Cys Leu Gly ThrSer Ala Ala 165 170 175 Lys Ala Leu Ile Tyr Gly Gly Glu Met Ala Ala AlaVal Ala Glu Val 180 185 190 Ser Glu Gln Leu Gly Lys Ser Leu Leu Lys PheCys Ser Gly Asp Leu 195 200 205 Gly Pro Glu Ser Ile Leu Pro Asp Thr GlnLeu Leu Asp Pro Met Leu 210 215 220 Ala Glu Ala Pro Thr Thr Pro Leu AlaGln Ala Pro Gly Lys Gly Met 225 230 235 240 Asp Asp Arg Leu Phe Tyr IleTyr Thr Ser Gly Thr Thr Gly Leu Pro 245 250 255 Lys Ala Ala Ile Val ValHis Ser Arg Tyr Tyr Arg Ile Ala Ala Phe 260 265 270 Gly His His Ser TyrSer Met Arg Ala Ala Asp Val Leu Tyr Asp Cys 275 280 285 Leu Pro Leu TyrHis Ser Ala Gly Asn Ile Met Gly Val Gly Gln Cys 290 295 300 Val Ile TyrGly Leu Thr Val Val Leu Arg Lys Lys Phe Ser Ala Ser 305 310 315 320 ArgPhe Trp Asp Asp Cys Val Lys Tyr Asn Cys Thr Val Val Gln Tyr 325 330 335Ile Gly Glu Ile Cys Arg Tyr Leu Leu Arg Gln Pro Val Arg Asp Val 340 345350 Glu Gln Arg His Arg Val Arg Leu Ala Val Gly Asn Gly Leu Arg Pro 355360 365 Ala Ile Trp Glu Glu Phe Thr Gln Arg Phe Gly Val Pro Gln Ile Gly370 375 380 Glu Phe Tyr Gly Ala Thr Glu Cys Asn Cys Ser Ile Ala Asn MetAsp 385 390 395 400 Gly Lys Val Gly Ser Cys Gly Phe Asn Ser Arg Ile LeuThr His Val 405 410 415 Tyr Pro Ile Arg Leu Val Lys Val Asn Glu Asp ThrMet Glu Pro Leu 420 425 430 Arg Asp Ser Glu Gly Leu Cys Ile Pro Cys GlnPro Gly Glu Pro Gly 435 440 445 Leu Leu Val Gly Gln Ile Asn Gln Gln AspPro Leu Arg Arg Phe Asp 450 455 460 Gly Tyr Val Ser Asp Ser Ala Thr AsnLys Lys Ile Ala His Ser Val 465 470 475 480 Phe Arg Lys Gly Asp Ser AlaTyr Leu Ser Gly Asp Val Leu Val Met 485 490 495 Asp Glu Leu Gly Tyr MetTyr Phe Arg Asp Arg Ser Gly Asp Thr Phe 500 505 510 Arg Trp Arg Gly GluAsn Val Ser Thr Thr Glu Val Glu Ala Val Leu 515 520 525 Ser Arg Leu LeuGly Gln Thr Asp Val Ala Val Tyr Gly Val Ala Val 530 535 540 Pro Gly ValGlu Gly Lys Ala Gly Met Ala Ala Ile Ala Asp Pro His 545 550 555 560 SerGln Leu Asp Pro Asn Ser Met Tyr Gln Glu Leu Gln Lys Val Leu 565 570 575Ala Ser Tyr Ala Arg Pro Ile Phe Leu Arg Leu Leu Pro Gln Val Asp 580 585590 Thr Thr Gly Thr Phe Lys Ile Gln Lys Thr Arg Leu Gln Arg Glu Gly 595600 605 Phe Asp Pro Arg Gln Thr Ser Asp Arg Leu Phe Phe Leu Asp Leu Lys610 615 620 Gln Gly Arg Tyr Leu Pro Leu Asp Glu Arg Val His Ala Arg IleCys 625 630 635 640 Ala Gly Asp Phe Ser Leu 645 <210> SEQ ID NO 93 <211>LENGTH: 620 <212> TYPE: PRT <213> ORGANISM: Mus musculus <220> FEATURE:<221> NAME/KEY: VARIANT <222> LOCATION: (1)...(620) <223> OTHERINFORMATION: Xaa = Any Amino Acid <220> FEATURE: <221> NAME/KEY: VARIANT<222> LOCATION: 285, 286, 287 <223> OTHER INFORMATION: Xaa = Any AminoAcid <400> SEQUENCE: 93 Met Leu Pro Val Leu Tyr Thr Gly Leu Ala Gly LeuLeu Leu Leu Pro 1 5 10 15 Leu Leu Leu Thr Cys Cys Cys Pro Tyr Leu LeuGln Asp Val Arg Tyr 20 25 30 Phe Leu Arg Leu Ala Asn Met Ala Arg Arg ValArg Ser Tyr Arg Gln 35 40 45 Arg Arg Pro Val Arg Thr Ile Leu Arg Ala PheLeu Glu Gln Ala Arg 50 55 60 Lys Thr Pro His Lys Pro Phe Leu Leu Phe ArgAsp Glu Thr Leu Thr 65 70 75 80 Tyr Ala Gln Val Asp Arg Arg Ser Asn GlnVal Ala Arg Ala Leu His 85 90 95 Asp Gln Leu Gly Leu Arg Gln Gly Asp CysVal Ala Leu Phe Met Gly 100 105 110 Asn Glu Pro Ala Tyr Val Trp Ile TrpLeu Gly Leu Leu Lys Leu Gly 115 120 125 Cys Pro Met Ala Cys Leu Asn TyrAsn Ile Arg Ala Lys Ser Leu Leu 130 135 140 His Cys Phe Gln Cys Cys GlyAla Lys Val Leu Leu Ala Ser Pro Asp 145 150 155 160 Leu Gln Glu Ala ValGlu Glu Val Leu Pro Thr Leu Lys Lys Asp Ala 165 170 175 Val Ser Val PheTyr Val Ser Arg Thr Ser Asn Thr Asn Gly Val Asp 180 185 190 Thr Ile LeuAsp Lys Val Asp Gly Val Ser Ala Glu Pro Thr Pro Glu 195 200 205 Ser TrpArg Ser Glu Val Thr Phe Thr Thr Pro Ala Val Tyr Ile Tyr 210 215 220 ThrSer Gly Thr Thr Gly Leu Pro Lys Ala Ala Thr Ile Asn His His 225 230 235240 Arg Leu Arg Tyr Gly Thr Gly Leu Ala Met Ser Ser Gly Ile Thr Ala 245250 255 Gln Asp Val Ile Tyr Thr Thr Met Pro Leu Tyr His Ser Ala Ala Leu260 265 270 Met Ile Gly Leu His Gly Cys Ile Val Val Gly Ala Xaa Xaa XaaLeu 275 280 285 Cys Asp Lys Phe Ser Ala Ser Gln Phe Trp Asp Asp Cys ArgLys Tyr 290 295 300 Asn Val Thr Val Ile Gln Tyr Ile Gly Glu Leu Leu ArgTyr Leu Cys 305 310 315 320 Asn Thr Pro Gln Lys Pro Asn Asp Arg Asp HisLys Val Lys Lys Ala 325 330 335 Leu Gly Asn Gly Leu Arg Gly Asp Val TrpArg Glu Phe Ile Lys Arg 340 345 350 Phe Gly Asp Ile His Val Tyr Glu PheTyr Ala Ser Thr Glu Gly Asn 355 360 365 Ile Gly Phe Val Asn Tyr Pro ArgLys Ile Gly Ala Val Gly Arg Ala 370 375 380 Asn Tyr Leu Gln Arg Lys ValAla Arg Tyr Glu Leu Ile Lys Tyr Asp 385 390 395 400 Val Glu Lys Asp GluPro Val Arg Asp Ala Asn Gly Tyr Cys Ile Lys 405 410 415 Val Pro Lys GlyGlu Val Gly Leu Leu Val Cys Lys Ile Thr Gln Leu 420 425 430 Thr Pro PheIle Gly Tyr Ala Gly Gly Lys Thr Gln Thr Glu Lys Lys 435 440 445 Lys LeuArg Asp Val Phe Lys Lys Gly Asp Ile Tyr Phe Asn Ser Gly 450 455 460 AspLeu Leu Met Ile Asp Arg Glu Asn Phe Val Tyr Phe His Asp Arg 465 470 475480 Val Gly Asp Thr Phe Arg Trp Lys Gly Glu Asn Val Ala Thr Thr Glu 485490 495 Val Ala Asp Ile Val Gly Leu Val Asp Phe Val Glu Glu Val Asn Val500 505 510 Tyr Gly Val Pro Val Pro Gly His Glu Gly Arg Ile Gly Met AlaSer 515 520 525 Leu Lys Ile Lys Glu Asn Tyr Glu Phe Asn Gly Lys Lys LeuPhe Gln 530 535 540 His Ile Ala Glu Tyr Leu Pro Ser Tyr Ala Arg Pro ArgPhe Leu Arg 545 550 555 560 Ile Gln Asp Thr Ile Glu Ile Thr Gly Thr PheLys His Arg Lys Val 565 570 575 Thr Leu Met Glu Glu Gly Phe Asn Pro ThrVal Ile Lys Asp Thr Leu 580 585 590 Tyr Phe Met Asp Asp Ala Glu Lys ThrPhe Val Pro Met Thr Glu Asn 595 600 605 Ile Tyr Asn Ala Ile Ile Asp LysThr Leu Lys Leu 610 615 620 <210> SEQ ID NO 94 <211> LENGTH: 613 <212>TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 94 Ala Ala AspPro Glu Ser Ser Glu Ser Gly Cys Ser Leu Ala Trp Arg 1 5 10 15 Leu AlaTyr Leu Ala Arg Glu Gln Pro Thr His Thr Phe Leu Ile His 20 25 30 Gly AlaGln Arg Phe Ser Tyr Ala Glu Ala Glu Arg Glu Ser Asn Arg 35 40 45 Ile AlaArg Ala Phe Leu Arg Ala Arg Gly Trp Thr Gly Gly Arg Arg 50 55 60 Gly SerGly Arg Gly Ser Thr Glu Glu Gly Ala Arg Val Ala Pro Pro 65 70 75 80 AlaGly Asp Ala Ala Ala Arg Gly Thr Thr Ala Pro Pro Leu Ala Pro 85 90 95 GlyAla Thr Val Ala Leu Leu Leu Pro Ala Gly Pro Asp Phe Leu Trp 100 105 110Ile Trp Phe Gly Leu Ala Lys Ala Gly Leu Arg Thr Ala Phe Val Pro 115 120125 Thr Ala Leu Arg Arg Gly Pro Leu Leu His Cys Leu Arg Ser Cys Gly 130135 140 Ala Ser Ala Leu Val Leu Ala Thr Glu Phe Leu Glu Ser Leu Glu Pro145 150 155 160 Asp Leu Pro Ala Leu Arg Ala Met Gly Leu His Leu Trp AlaThr Gly 165 170 175 Pro Glu Thr Asn Val Ala Gly Ile Ser Asn Leu Leu SerGlu Ala Ala 180 185 190 Asp Gln Val Asp Glu Pro Val Pro Gly Tyr Leu SerAla Pro Gln Asn 195 200 205 Ile Met Asp Thr Cys Leu Tyr Ile Phe Thr SerGly Thr Thr Gly Leu 210 215 220 Pro Lys Ala Ala Arg Ile Ser His Leu LysVal Leu Gln Cys Gln Gly 225 230 235 240 Phe Tyr His Leu Cys Gly Val HisGln Glu Asp Val Ile Tyr Leu Ala 245 250 255 Leu Pro Leu Tyr His Met SerGly Ser Leu Leu Gly Ile Val Gly Cys 260 265 270 Leu Gly Ile Gly Ala ThrVal Val Leu Lys Pro Lys Phe Ser Ala Ser 275 280 285 Gln Phe Trp Asp AspCys Gln Lys His Arg Val Thr Val Phe Gln Tyr 290 295 300 Ile Gly Glu LeuCys Arg Tyr Leu Val Asn Gln Pro Pro Ser Lys Ala 305 310 315 320 Glu PheAsp His Lys Val Arg Leu Ala Val Gly Ser Gly Leu Arg Pro 325 330 335 AspThr Trp Glu Arg Phe Leu Arg Arg Phe Gly Pro Leu Gln Ile Leu 340 345 350Glu Thr Tyr Gly Met Thr Glu Gly Asn Val Ala Thr Phe Asn Tyr Thr 355 360365 Gly Arg Gln Gly Ala Val Gly Arg Ala Ser Trp Leu Tyr Lys His Ile 370375 380 Phe Pro Phe Ser Leu Ile Arg Tyr Asp Val Met Thr Gly Glu Pro Ile385 390 395 400 Arg Asn Ala Gln Gly His Cys Met Thr Thr Ser Pro Gly GluPro Gly 405 410 415 Leu Leu Val Ala Pro Val Ser Gln Gln Ser Pro Phe LeuGly Tyr Ala 420 425 430 Gly Ala Pro Glu Leu Ala Lys Asp Lys Leu Leu LysAsp Val Phe Trp 435 440 445 Ser Gly Asp Val Phe Phe Asn Thr Gly Asp LeuLeu Val Cys Asp Glu 450 455 460 Gln Gly Phe Leu His Phe His Asp Arg ThrGly Asp Thr Ile Arg Trp 465 470 475 480 Lys Gly Glu Asn Val Ala Thr ThrGlu Val Ala Glu Val Leu Glu Thr 485 490 495 Leu Asp Phe Leu Gln Glu ValAsn Ile Tyr Gly Val Thr Val Pro Gly 500 505 510 His Glu Gly Arg Ala GlyMet Ala Ala Leu Ala Leu Arg Pro Pro Gln 515 520 525 Ala Leu Asn Leu ValGln Leu Tyr Ser His Val Ser Glu Asn Leu Pro 530 535 540 Pro Tyr Ala ArgPro Arg Phe Leu Arg Leu Gln Glu Ser Leu Ala Thr 545 550 555 560 Thr GluThr Phe Lys Gln Gln Lys Val Arg Met Ala Asn Glu Gly Phe 565 570 575 AspPro Ser Val Leu Ser Asp Pro Leu Tyr Val Leu Asp Gln Asp Ile 580 585 590Gly Ala Tyr Leu Pro Leu Thr Pro Ala Arg Tyr Ser Ala Leu Leu Ser 595 600605 Gly Asp Leu Arg Ile 610 <210> SEQ ID NO 95 <211> LENGTH: 506 <212>TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 95 His Ala SerAla His Ala Ser Gly Met Ala Lys Leu Gly Val Glu Ala 1 5 10 15 Ala LeuIle Asn Thr Asn Leu Arg Arg Asp Ala Leu Arg His Cys Leu 20 25 30 Asp ThrSer Lys Ala Arg Ala Leu Ile Phe Gly Ser Glu Met Ala Ser 35 40 45 Ala IleCys Glu Ile His Ala Ser Leu Glu Pro Thr Leu Ser Leu Phe 50 55 60 Cys SerGly Ser Trp Glu Pro Ser Thr Val Pro Val Ser Thr Glu His 65 70 75 80 LeuAsp Pro Leu Leu Glu Asp Ala Pro Lys His Leu Pro Ser His Pro 85 90 95 AspLys Gly Phe Thr Asp Lys Leu Phe Tyr Ile Tyr Thr Ser Gly Thr 100 105 110Thr Gly Leu Pro Lys Ala Ala Ile Val Val His Ser Arg Tyr Tyr Arg 115 120125 Met Ala Ser Leu Val Tyr Tyr Gly Phe Arg Met Arg Pro Asp Asp Ile 130135 140 Val Tyr Asp Cys Leu Pro Leu Tyr His Ser Ser Arg Lys His Arg Gly145 150 155 160 Asp Trp Gln Cys Leu Leu His Gly Met Thr Val Val Ile ArgLys Lys 165 170 175 Phe Ser Ala Ser Arg Phe Trp Asp Asp Cys Ile Lys TyrAsn Cys Thr 180 185 190 Val Val Gln Tyr Ile Gly Glu Leu Cys Arg Tyr LeuLeu Asn Gln Pro 195 200 205 Pro Arg Glu Ala Glu Ser Arg His Lys Val ArgMet Ala Leu Gly Asn 210 215 220 Gly Leu Arg Gln Ser Ile Trp Thr Asp PheSer Ser Arg Phe His Ile 225 230 235 240 Pro Gln Val Ala Glu Phe Tyr GlyAla Thr Glu Cys Asn Cys Ser Leu 245 250 255 Gly Asn Phe Asp Ser Arg ValGly Ala Cys Gly Phe Asn Ser Arg Ile 260 265 270 Leu Ser Phe Val Tyr ProIle Arg Leu Val Arg Val Asn Glu Asp Thr 275 280 285 Met Glu Leu Ile ArgGly Pro Asp Gly Val Cys Ile Pro Cys Gln Pro 290 295 300 Gly Gln Pro GlyGln Leu Val Gly Arg Ile Ile Gln Gln Asp Pro Leu 305 310 315 320 Arg ArgPhe Asp Gly Tyr Leu Asn Gln Gly Ala Asn Asn Lys Lys Ile 325 330 335 AlaAsn Asp Val Phe Lys Lys Gly Asp Gln Ala Tyr Leu Thr Gly Asp 340 345 350Val Leu Val Met Asp Glu Leu Gly Tyr Leu Tyr Phe Arg Asp Arg Thr 355 360365 Gly Asp Thr Phe Arg Trp Lys Gly Glu Asn Val Ser Thr Thr Glu Val 370375 380 Glu Gly Thr Leu Ser Arg Leu Leu His Met Ala Asp Val Ala Val Tyr385 390 395 400 Gly Val Glu Val Pro Gly Thr Glu Gly Arg Ala Gly Met AlaAla Val 405 410 415 Ala Ser Pro Ile Ser Asn Cys Asp Leu Glu Ser Phe AlaGln Thr Leu 420 425 430 Lys Lys Glu Leu Pro Leu Tyr Ala Arg Pro Ile PheLeu Arg Phe Leu 435 440 445 Pro Glu Leu His Lys Thr Gly Thr Phe Lys PheGln Lys Thr Glu Leu 450 455 460 Arg Lys Glu Gly Phe Asp Pro Ser Val ValLys Asp Pro Leu Phe Tyr 465 470 475 480 Leu Asp Ala Arg Lys Gly Cys TyrVal Ala Leu Asp Gln Glu Ala Tyr 485 490 495 Thr Arg Ile Gln Ala Gly GluGlu Lys Leu 500 505 <210> SEQ ID NO 96 <211> LENGTH: 662 <212> TYPE: PRT<213> ORGANISM: Mus musculus <400> SEQUENCE: 96 Met Ala Leu Ala Leu ArgTrp Phe Leu Gly Asp Pro Thr Cys Leu Val 1 5 10 15 Leu Leu Gly Leu AlaLeu Leu Gly Arg Pro Trp Ile Ser Ser Trp Met 20 25 30 Pro His Trp Leu SerLeu Val Gly Ala Ala Leu Thr Leu Phe Leu Leu 35 40 45 Pro Leu Gln Pro ProPro Gly Leu Arg Trp Leu His Lys Asp Val Ala 50 55 60 Phe Thr Phe Lys MetLeu Phe Tyr Gly Leu Lys Phe Arg Arg Arg Leu 65 70 75 80 Asn Lys His ProPro Glu Thr Phe Val Asp Ala Leu Glu Arg Gln Ala 85 90 95 Leu Ala Trp ProAsp Arg Val Ala Leu Val Cys Thr Gly Ser Glu Gly 100 105 110 Ser Ser IleThr Asn Ser Gln Leu Asp Ala Arg Ser Cys Gln Ala Ala 115 120 125 Trp ValLeu Lys Ala Lys Leu Lys Asp Ala Val Ile Gln Asn Thr Arg 130 135 140 AspAla Ala Ala Ile Leu Val Leu Pro Ser Lys Thr Ile Ser Ala Leu 145 150 155160 Ser Val Phe Leu Gly Leu Ala Lys Leu Gly Cys Pro Val Ala Trp Ile 165170 175 Asn Pro His Ser Arg Gly Met Pro Leu Leu His Ser Val Arg Ser Ser180 185 190 Gly Ala Ser Val Leu Ile Val Asp Pro Asp Leu Gln Glu Asn LeuGlu 195 200 205 Glu Val Leu Pro Lys Leu Leu Ala Glu Asn Ile His Cys PheTyr Leu 210 215 220 Gly His Ser Ser Pro Thr Pro Gly Val Glu Ala Leu GlyAla Ser Leu 225 230 235 240 Asp Ala Ala Pro Ser Asp Pro Val Pro Ala SerLeu Arg Ala Thr Ile 245 250 255 Lys Trp Lys Ser Pro Ala Ile Phe Ile PheThr Ser Gly Thr Thr Gly 260 265 270 Leu Pro Lys Pro Ala Ile Leu Ser HisGlu Arg Val Ile Gln Val Ser 275 280 285 Asn Val Leu Ser Phe Cys Gly CysArg Ala Asp Asp Val Val Tyr Asp 290 295 300 Val Leu Pro Leu Tyr His ThrIle Gly Leu Val Leu Gly Phe Leu Gly 305 310 315 320 Cys Leu Gln Val GlyAla Thr Cys Val Leu Ala Pro Lys Phe Ser Ala 325 330 335 Ser Arg Phe TrpAla Glu Cys Arg Gln His Gly Val Thr Val Ile Leu 340 345 350 Tyr Val GlyGlu Ile Leu Arg Tyr Leu Cys Asn Val Pro Glu Gln Pro 355 360 365 Glu AspLys Ile His Thr Val Arg Leu Ala Met Gly Thr Gly Leu Arg 370 375 380 AlaAsn Val Trp Lys Asn Phe Gln Gln Arg Phe Gly Pro Ile Arg Ile 385 390 395400 Trp Glu Phe Tyr Gly Ser Thr Glu Gly Asn Val Gly Leu Met Asn Tyr 405410 415 Val Gly His Cys Gly Ala Val Gly Arg Thr Ser Cys Ile Leu Arg Met420 425 430 Leu Thr Pro Phe Glu Leu Val Gln Phe Asp Ile Glu Thr Ala GluPro 435 440 445 Leu Arg Asp Lys Gln Gly Phe Cys Ile Pro Val Glu Pro GlyLys Pro 450 455 460 Gly Leu Leu Leu Thr Lys Val Arg Lys Asn Gln Pro PheLeu Gly Tyr 465 470 475 480 Arg Gly Ser Gln Ala Glu Ser Asn Arg Lys LeuVal Ala Asn Val Arg 485 490 495 Arg Val Gly Asp Leu Tyr Phe Asn Thr GlyAsp Val Leu Thr Leu Asp 500 505 510 Gln Glu Gly Phe Phe Tyr Phe Gln AspArg Leu Gly Asp Thr Phe Arg 515 520 525 Trp Lys Gly Glu Asn Val Ser ThrGly Glu Val Glu Cys Val Leu Ser 530 535 540 Ser Leu Asp Phe Leu Glu GluVal Asn Val Tyr Gly Val Pro Val Pro 545 550 555 560 Gly Cys Glu Gly LysVal Gly Met Ala Ala Val Lys Leu Ala Pro Gly 565 570 575 Lys Thr Phe AspGly Gln Lys Leu Tyr Gln His Val Arg Ser Trp Leu 580 585 590 Pro Ala TyrAla Thr Pro His Phe Ile Arg Ile Gln Asp Ser Leu Glu 595 600 605 Ile ThrAsn Thr Tyr Lys Leu Val Lys Ser Arg Leu Val Arg Glu Gly 610 615 620 PheAsp Val Gly Ile Ile Ala Asp Pro Leu Tyr Ile Leu Asp Asn Lys 625 630 635640 Ala Gln Thr Phe Arg Ser Leu Met Pro Asp Val Tyr Gln Ala Val Cys 645650 655 Glu Gly Thr Trp Asn Leu 660 <210> SEQ ID NO 97 <211> LENGTH: 650<212> TYPE: PRT <213> ORGANISM: Caenorhabditis elegans <400> SEQUENCE:97 Met Lys Leu Glu Glu Leu Val Thr Val Met Leu Leu Thr Val Ala Val 1 510 15 Ile Ala Gln Asn Leu Pro Ile Gly Val Ile Leu Ala Gly Val Leu Ile 2025 30 Leu Tyr Ile Thr Val Val His Gly Asp Phe Ile Tyr Arg Ser Tyr Leu 3540 45 Thr Leu Asn Arg Asp Leu Thr Gly Leu Ala Leu Ile Ile Glu Val Lys 5055 60 Ile Asp Leu Trp Trp Arg Leu His Gln Asn Lys Gly Ile His Glu Leu 6570 75 80 Phe Leu Asp Ile Val Lys Lys Asn Pro Asn Lys Pro Ala Met Ile Asp85 90 95 Ile Glu Thr Asn Thr Thr Glu Thr Tyr Ala Glu Phe Asn Ala His Cys100 105 110 Asn Arg Tyr Ala Asn Tyr Phe Gln Gly Leu Gly Tyr Arg Ser GlyAsp 115 120 125 Val Val Ala Leu Tyr Met Glu Asn Ser Val Glu Phe Val AlaAla Trp 130 135 140 Met Gly Leu Ala Lys Ile Gly Val Val Thr Ala Trp IleAsn Ser Asn 145 150 155 160 Leu Lys Arg Glu Gln Leu Val His Cys Ile ThrAla Ser Lys Thr Lys 165 170 175 Ala Ile Ile Thr Ser Val Thr Leu Gln AsnIle Met Leu Asp Ala Ile 180 185 190 Asp Gln Lys Leu Phe Asp Val Glu GlyIle Glu Val Tyr Ser Val Gly 195 200 205 Glu Pro Lys Lys Asn Ser Gly PheLys Asn Leu Lys Lys Lys Leu Asp 210 215 220 Ala Gln Ile Thr Thr Glu ProLys Thr Leu Asp Ile Val Asp Phe Lys 225 230 235 240 Ser Ile Leu Cys PheIle Tyr Thr Ser Gly Thr Thr Gly Met Pro Lys 245 250 255 Ala Ala Val MetLys His Phe Arg Tyr Tyr Ser Ile Ala Val Gly Ala 260 265 270 Ala Lys SerPhe Gly Ile Arg Pro Ser Asp Arg Met Tyr Val Ser Met 275 280 285 Pro IleTyr His Thr Ala Ala Gly Ile Leu Gly Val Gly Gln Ala Leu 290 295 300 LeuGly Gly Ser Ser Cys Val Ile Arg Lys Lys Phe Ser Ala Ser Asn 305 310 315320 Phe Trp Arg Asp Cys Val Lys Tyr Asp Cys Thr Val Ser Gln Tyr Ile 325330 335 Gly Glu Ile Cys Arg Tyr Leu Leu Ala Gln Pro Val Val Glu Glu Glu340 345 350 Ser Arg His Arg Met Arg Leu Leu Val Gly Asn Gly Leu Arg AlaGlu 355 360 365 Ile Trp Gln Pro Phe Val Asp Arg Phe Arg Val Arg Ile GlyGlu Leu 370 375 380 Tyr Gly Ser Thr Glu Gly Thr Ser Ser Leu Val Asn IleAsp Gly His 385 390 395 400 Val Gly Ala Cys Gly Phe Leu Pro Ile Ser ProLeu Thr Lys Lys Met 405 410 415 His Pro Val Arg Leu Ile Lys Val Asp AspVal Thr Gly Glu Ala Ile 420 425 430 Arg Thr Ser Asp Gly Leu Cys Ile AlaCys Asn Pro Gly Glu Ser Gly 435 440 445 Ala Met Val Ser Thr Ile Arg LysAsn Asn Pro Leu Leu Gln Phe Glu 450 455 460 Gly Tyr Leu Asn Lys Lys GluThr Asn Lys Lys Ile Ile Arg Asp Val 465 470 475 480 Phe Ala Lys Gly AspSer Cys Phe Leu Thr Gly Asp Leu Leu His Trp 485 490 495 Asp Arg Leu GlyTyr Val Tyr Phe Lys Asp Arg Thr Gly Asp Thr Phe 500 505 510 Arg Trp LysGly Glu Asn Val Ser Thr Thr Glu Val Glu Ala Ile Leu 515 520 525 His ProIle Thr Gly Leu Ser Asp Ala Thr Val Tyr Gly Val Glu Val 530 535 540 ProGln Arg Glu Gly Arg Val Gly Met Ala Ser Val Val Arg Val Val 545 550 555560 Ser His Glu Glu Asp Glu Thr Gln Phe Val His Arg Val Gly Ala Arg 565570 575 Leu Ala Ser Ser Leu Thr Ser Tyr Ala Ile Pro Gln Phe Met Arg Ile580 585 590 Cys Gln Asp Val Glu Lys Thr Gly Thr Phe Lys Leu Val Lys ThrAsn 595 600 605 Leu Gln Arg Leu Gly Ile Met Asp Ala Pro Ser Asp Ser IleTyr Ile 610 615 620 Tyr Asn Ser Glu Asn Arg Asn Phe Val Pro Phe Asp AsnAsp Leu Arg 625 630 635 640 Cys Lys Val Ser Leu Gly Ser Tyr Pro Phe 645650 <210> SEQ ID NO 98 <211> LENGTH: 623 <212> TYPE: PRT <213> ORGANISM:Saccharomyces cerevisiae <400> SEQUENCE: 98 Met Ser Pro Ile Gln Val ValVal Phe Ala Leu Ser Arg Ile Phe Leu 1 5 10 15 Leu Leu Phe Arg Leu IleLys Leu Ile Ile Thr Pro Ile Gln Lys Ser 20 25 30 Leu Gly Tyr Leu Phe GlyAsn Tyr Phe Asp Glu Leu Asp Arg Lys Tyr 35 40 45 Arg Tyr Lys Glu Asp TrpTyr Ile Ile Pro Tyr Phe Leu Lys Ser Val 50 55 60 Phe Cys Tyr Ile Ile AspVal Arg Arg His Arg Phe Gln Asn Trp Tyr 65 70 75 80 Leu Phe Ile Lys GlnVal Gln Gln Asn Gly Asp His Leu Ala Ile Ser 85 90 95 Tyr Thr Arg Pro MetAla Glu Lys Gly Glu Phe Gln Leu Glu Thr Phe 100 105 110 Thr Tyr Ile GluThr Tyr Asn Ile Val Leu Arg Leu Ser His Ile Leu 115 120 125 His Phe AspTyr Asn Val Gln Ala Gly Asp Tyr Val Ala Ile Asp Cys 130 135 140 Thr AsnLys Pro Leu Phe Val Phe Leu Trp Leu Ser Leu Trp Asn Ile 145 150 155 160Gly Ala Ile Pro Ala Phe Leu Asn Tyr Asn Thr Lys Gly Thr Pro Leu 165 170175 Val His Ser Leu Lys Ile Ser Asn Ile Thr Gln Val Phe Ile Asp Pro 180185 190 Asp Ala Ser Asn Pro Ile Arg Glu Ser Glu Glu Glu Ile Lys Asn Ala195 200 205 Leu Pro Asp Val Lys Leu Asn Tyr Leu Glu Glu Gln Asp Leu MetHis 210 215 220 Glu Leu Leu Asn Ser Gln Ser Pro Glu Phe Leu Gln Gln AspAsn Val 225 230 235 240 Arg Thr Pro Leu Gly Leu Thr Asp Phe Lys Pro SerMet Leu Ile Tyr 245 250 255 Thr Ser Gly Thr Thr Gly Leu Pro Lys Ser AlaIle Met Ser Trp Arg 260 265 270 Lys Ser Ser Val Gly Cys Gln Val Phe GlyHis Val Leu His Met Thr 275 280 285 Asn Glu Ser Thr Val Phe Thr Ala MetPro Leu Phe His Ser Thr Ala 290 295 300 Ala Leu Leu Gly Ala Cys Ala IleLeu Ser His Gly Gly Cys Leu Ala 305 310 315 320 Leu Ser His Lys Phe SerAla Ser Thr Phe Trp Lys Gln Val Tyr Leu 325 330 335 Thr Gly Ala Thr HisIle Gln Tyr Val Gly Glu Val Cys Arg Tyr Leu 340 345 350 Leu His Thr ProIle Ser Lys Tyr Glu Lys Met His Lys Val Lys Val 355 360 365 Ala Tyr GlyAsn Gly Leu Arg Pro Asp Ile Trp Gln Asp Phe Arg Lys 370 375 380 Arg PheAsn Ile Glu Val Ile Gly Glu Phe Tyr Ala Ala Thr Glu Ala 385 390 395 400Pro Phe Ala Thr Thr Thr Phe Gln Lys Gly Asp Phe Gly Ile Gly Ala 405 410415 Cys Arg Asn Tyr Gly Thr Ile Ile Gln Trp Phe Leu Ser Phe Gln Gln 420425 430 Thr Leu Val Arg Met Asp Pro Asn Asp Asp Ser Val Ile Tyr Arg Asn435 440 445 Ser Lys Gly Phe Cys Glu Val Ala Pro Val Gly Glu Pro Gly GluMet 450 455 460 Leu Met Arg Ile Phe Phe Pro Lys Lys Pro Glu Thr Ser PheGln Gly 465 470 475 480 Tyr Leu Gly Asn Ala Lys Glu Thr Lys Ser Lys ValVal Arg Asp Val 485 490 495 Phe Arg Arg Gly Asp Ala Trp Tyr Arg Cys GlyAsp Leu Leu Lys Ala 500 505 510 Asp Glu Tyr Gly Leu Trp Tyr Phe Leu AspArg Met Gly Asp Thr Phe 515 520 525 Arg Trp Lys Ser Glu Asn Val Ser ThrThr Glu Val Glu Asp Gln Leu 530 535 540 Thr Ala Ser Asn Lys Glu Gln TyrAla Gln Val Leu Val Val Gly Ile 545 550 555 560 Lys Val Pro Lys Tyr GluGly Arg Ala Gly Phe Ala Val Ile Lys Leu 565 570 575 Thr Asp Asn Ser LeuAsp Ile Thr Ala Lys Thr Lys Leu Leu Asn Asp 580 585 590 Ser Leu Ser ArgLeu Asn Leu Pro Ser Tyr Ala Met Pro Leu Phe Val 595 600 605 Lys Phe ValAsp Glu Ile Lys Met Thr Asp Asn Leu Ile Lys Phe 610 615 620 <210> SEQ IDNO 99 <211> LENGTH: 597 <212> TYPE: PRT <213> ORGANISM: Mycobacteriumtuberculosis <400> SEQUENCE: 99 Met Ser Asp Tyr Tyr Gly Gly Ala His ThrThr Val Arg Leu Ile Asp 1 5 10 15 Leu Ala Thr Arg Met Pro Arg Val LeuAla Asp Thr Pro Val Ile Val 20 25 30 Arg Gly Ala Met Thr Gly Leu Leu AlaArg Pro Asn Ser Lys Ala Ser 35 40 45 Ile Gly Thr Val Phe Gln Asp Arg AlaAla Arg Tyr Gly Asp Arg Val 50 55 60 Phe Leu Lys Phe Gly Asp Gln Gln LeuThr Tyr Arg Asp Ala Asn Ala 65 70 75 80 Thr Ala Asn Arg Tyr Ala Ala ValLeu Ala Ala Arg Gly Val Gly Pro 85 90 95 Gly Asp Val Val Gly Ile Met LeuArg Asn Ser Pro Ser Thr Val Leu 100 105 110 Ala Met Leu Ala Thr Val LysCys Gly Ala Ile Ala Gly Met Leu Asn 115 120 125 Tyr His Gln Arg Gly GluVal Leu Ala His Ser Leu Gly Leu Leu Asp 130 135 140 Ala Lys Val Leu IleAla Glu Ser Asp Leu Val Ser Ala Val Ala Glu 145 150 155 160 Cys Gly AlaSer Arg Gly Arg Val Ala Gly Asp Val Leu Thr Val Glu 165 170 175 Asp ValGlu Arg Phe Ala Thr Thr Ala Pro Ala Thr Asn Pro Ala Ser 180 185 190 AlaSer Ala Val Gln Ala Lys Asp Thr Ala Phe Tyr Ile Phe Thr Ser 195 200 205Gly Thr Thr Gly Phe Pro Lys Ala Ser Val Met Thr His His Arg Trp 210 215220 Leu Arg Ala Leu Ala Val Phe Gly Gly Met Gly Leu Arg Leu Lys Gly 225230 235 240 Ser Asp Thr Leu Tyr Ser Cys Leu Pro Leu Tyr His Asn Asn AlaLeu 245 250 255 Thr Val Ala Val Ser Ser Val Ile Asn Ser Gly Ala Thr LeuAla Leu 260 265 270 Gly Lys Ser Phe Ser Ala Ser Arg Phe Trp Asp Glu ValIle Ala Asn 275 280 285 Arg Ala Thr Ala Phe Val Tyr Ile Gly Glu Ile CysArg Tyr Leu Leu 290 295 300 Asn Gln Pro Ala Lys Pro Thr Asp Arg Ala HisGln Val Arg Val Ile 305 310 315 320 Cys Gly Asn Gly Leu Arg Pro Glu IleTrp Asp Glu Phe Thr Thr Arg 325 330 335 Phe Gly Val Ala Arg Val Cys GluPhe Tyr Ala Ala Ser Glu Gly Asn 340 345 350 Ser Ala Phe Ile Asn Ile PheAsn Val Pro Arg Thr Ala Gly Val Ser 355 360 365 Pro Met Pro Leu Ala PheVal Glu Tyr Asp Leu Asp Thr Gly Asp Pro 370 375 380 Leu Arg Asp Ala SerGly Arg Val Arg Arg Val Pro Asp Gly Glu Pro 385 390 395 400 Gly Leu LeuLeu Ser Arg Val Asn Arg Leu Gln Pro Phe Asp Gly Tyr 405 410 415 Thr AspPro Val Ala Ser Glu Lys Lys Leu Val Arg Asn Ala Phe Arg 420 425 430 AspGly Asp Cys Trp Phe Asn Thr Gly Asp Val Met Ser Pro Gln Gly 435 440 445Met Gly His Ala Ala Phe Val Asp Arg Leu Gly Asp Thr Phe Arg Trp 450 455460 Lys Gly Glu Asn Val Ala Thr Thr Gln Val Glu Ala Ala Leu Ala Ser 465470 475 480 Asp Gln Thr Val Glu Glu Cys Thr Val Tyr Gly Val Gln Ile ProArg 485 490 495 Thr Gly Gly Arg Ala Gly Met Ala Ala Ile Thr Leu Arg AlaGly Ala 500 505 510 Glu Phe Asp Gly Gln Ala Leu Ala Arg Thr Val Tyr GlyHis Leu Pro 515 520 525 Gly Tyr Ala Leu Pro Leu Phe Val Arg Val Val GlySer Leu Ala His 530 535 540 Thr Thr Thr Phe Lys Ser Arg Lys Val Glu LeuArg Asn Gln Ala Tyr 545 550 555 560 Gly Ala Asp Ile Glu Asp Pro Leu TyrVal Leu Ala Gly Pro Asp Glu 565 570 575 Gly Tyr Val Pro Tyr Tyr Ala GluTyr Pro Glu Glu Val Ser Leu Gly 580 585 590 Arg Arg Pro Gln Gly 595<210> SEQ ID NO 100 <211> LENGTH: 304 <212> TYPE: PRT <213> ORGANISM:concensus FATP signature sequence <400> SEQUENCE: 100 Tyr Ile Tyr ThrSer Gly Thr Thr Gly Leu Pro Lys Ala Ala Ile Ile 1 5 10 15 Val His SerArg Tyr Tyr Arg Gly Ala Ala Leu His Ser Gly Arg Met 20 25 30 Arg Pro AspVal Val Tyr Asp Cys Leu Pro Leu Tyr His Ser Ala Ala 35 40 45 Leu Ile LeuGly Ile Gly Gln Cys Leu Leu His Gly Ala Thr Val Val 50 55 60 Leu Arg LysLys Phe Ser Ala Ser Arg Phe Trp Asp Asp Cys Val Lys 65 70 75 80 Tyr AsnVal Thr Val Ile Gln Tyr Ile Gly Glu Leu Cys Arg Tyr Leu 85 90 95 Leu AsnGln Pro Pro Arg Pro Ala Glu Arg Arg His Lys Val Arg Leu 100 105 110 AlaVal Gly Asn Gly Leu Arg Pro Asp Ile Trp Glu Glu Phe Val Ser 115 120 125Arg Phe Gly Ile Pro Gln Ile Gly Glu Phe Tyr Gly Ala Thr Glu Gly 130 135140 Asn Cys Ser Leu Met Asn Tyr Asp Gly Lys Val Gly Ala Cys Gly Ser 145150 155 160 Arg Ile Leu Lys Lys Val Tyr Pro Ile Arg Leu Val Lys Val AspGlu 165 170 175 Asp Thr Gly Glu Pro Ile Arg Asp Ala Gln Gly Leu Cys IlePro Cys 180 185 190 Gln Pro Gly Glu Pro Gly Leu Leu Val Gly Arg Ile AsnGln Gln Asp 195 200 205 Pro Phe Arg Gly Phe Gly Tyr Gly Ser Glu Gly AlaThr Asn Lys Lys 210 215 220 Ile Ala Arg Asp Val Phe Lys Lys Gly Asp ValAla Phe Asn Thr Gly 225 230 235 240 Asp Val Leu Val Met Asp Glu Leu GlyTyr Leu Tyr Phe Arg Asp Arg 245 250 255 Thr Gly Asp Thr Phe Arg Trp LysGly Glu Asn Val Ser Thr Thr Glu 260 265 270 Val Glu Gly Val Leu Ser ArgLeu Asp Phe Val Ala Glu Val Asn Val 275 280 285 Tyr Gly Val Thr Val ProGly His Glu Gly Arg Ala Gly Met Ala Ala 290 295 300 <210> SEQ ID NO 101<211> LENGTH: 2166 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220>FEATURE: <221> NAME/KEY: CDS <222> LOCATION: (19)...(2124) <400>SEQUENCE: 101 cgacccacgc gtccgggg atg ttt gcg agc ggc tgg aac cag acggtg ccg 51 Met Phe Ala Ser Gly Trp Asn Gln Thr Val Pro 1 5 10 ata gaggaa gcg ggc tcc atg gct gcc ctc ctg ctg ctg ccc ctg ctg 99 Ile Glu GluAla Gly Ser Met Ala Ala Leu Leu Leu Leu Pro Leu Leu 15 20 25 ctg ttg ctaccg ctg ctg ctg ctg ctg aag cta cac ctc tgg ccg cag 147 Leu Leu Leu ProLeu Leu Leu Leu Leu Lys Leu His Leu Trp Pro Gln 30 35 40 ttg cgc tgg cttccg gcg gac ttg gcc ttt gcg gtg cga gct ctg tgc 195 Leu Arg Trp Leu ProAla Asp Leu Ala Phe Ala Val Arg Ala Leu Cys 45 50 55 tgc aaa agg gct cttcga gct cgc gcc ctg gcc gcg gct gcc gcc gac 243 Cys Lys Arg Ala Leu ArgAla Arg Ala Leu Ala Ala Ala Ala Ala Asp 60 65 70 75 ccg gaa ggt ccc gagggg ggc tgc agc ctg gcc tgg cgc ctc gcg gaa 291 Pro Glu Gly Pro Glu GlyGly Cys Ser Leu Ala Trp Arg Leu Ala Glu 80 85 90 ctg gcc cag cag cgc gccgcg cac acc ttt ctc att cac ggc tcg cgg 339 Leu Ala Gln Gln Arg Ala AlaHis Thr Phe Leu Ile His Gly Ser Arg 95 100 105 cgc ttt agc tac tca gaggcg gag cgc gag agt aac agg gct gca cgc 387 Arg Phe Ser Tyr Ser Glu AlaGlu Arg Glu Ser Asn Arg Ala Ala Arg 110 115 120 gcc ttc cta cgt gcg ctaggc tgg gac tgg gga ccc gac ggc ggc gac 435 Ala Phe Leu Arg Ala Leu GlyTrp Asp Trp Gly Pro Asp Gly Gly Asp 125 130 135 agc ggc gag ggg agc gctgga gaa ggc gag cgg gca gcg ccg gga gcc 483 Ser Gly Glu Gly Ser Ala GlyGlu Gly Glu Arg Ala Ala Pro Gly Ala 140 145 150 155 gga gat gca gcg gccgga agc ggc gcg gag ttt gcc gga ggg gac ggt 531 Gly Asp Ala Ala Ala GlySer Gly Ala Glu Phe Ala Gly Gly Asp Gly 160 165 170 gcc gcc aga ggt ggagga gag ccc gcc gcc cct ctg tca cct gga gca 579 Ala Ala Arg Gly Gly GlyGlu Pro Ala Ala Pro Leu Ser Pro Gly Ala 175 180 185 act gtg gcg ctg ctcctc ccc gct ggc cca gag ttt ctg tgg ctc tgg 627 Thr Val Ala Leu Leu LeuPro Ala Gly Pro Glu Phe Leu Trp Leu Trp 190 195 200 ttc ggg ctg gcc aaggcc ggc ctg cgc act gcc ttt gtg ccc acc gcc 675 Phe Gly Leu Ala Lys AlaGly Leu Arg Thr Ala Phe Val Pro Thr Ala 205 210 215 ctg cgc cgg ggc cccctg ctg cac tgc ctc cgc agc tgc ggc gcg cgc 723 Leu Arg Arg Gly Pro LeuLeu His Cys Leu Arg Ser Cys Gly Ala Arg 220 225 230 235 gcg ctg gtg ctggcg cca gag ttt ctg gag tcc ctg gag ccg gac ctg 771 Ala Leu Val Leu AlaPro Glu Phe Leu Glu Ser Leu Glu Pro Asp Leu 240 245 250 ccc gcc ctg agagcc atg ggg ctc cac ctg tgg gct gca ggc cca gga 819 Pro Ala Leu Arg AlaMet Gly Leu His Leu Trp Ala Ala Gly Pro Gly 255 260 265 acc cac cct gctgga att agc gat ttg ctg gct gaa gtg tcc gct gaa 867 Thr His Pro Ala GlyIle Ser Asp Leu Leu Ala Glu Val Ser Ala Glu 270 275 280 gtg gat ggg ccagtg cca gga tac ctc tct tcc ccc cag agc ata aca 915 Val Asp Gly Pro ValPro Gly Tyr Leu Ser Ser Pro Gln Ser Ile Thr 285 290 295 gac acg tgc ctgtac atc ttc acc tct ggc acc acg ggc ctc ccc aag 963 Asp Thr Cys Leu TyrIle Phe Thr Ser Gly Thr Thr Gly Leu Pro Lys 300 305 310 315 gct gct cggatc agt cat ctg aag atc ctg caa tgc cag ggc ttc tat 1011 Ala Ala Arg IleSer His Leu Lys Ile Leu Gln Cys Gln Gly Phe Tyr 320 325 330 cag ctg tgtggt gtc cac cag gaa gat gtg atc tac ctc gcc ctc cca 1059 Gln Leu Cys GlyVal His Gln Glu Asp Val Ile Tyr Leu Ala Leu Pro 335 340 345 ctc tac cacatg tcc ggt tcc ctg ctg ggc atc gtg ggc tgc atg ggc 1107 Leu Tyr His MetSer Gly Ser Leu Leu Gly Ile Val Gly Cys Met Gly 350 355 360 att ggg gccaca gtg gtg ctg aaa tcc aag ttc tcg gct ggt cag ttc 1155 Ile Gly Ala ThrVal Val Leu Lys Ser Lys Phe Ser Ala Gly Gln Phe 365 370 375 tgg gaa gattgc cag cag cac agg gtg acg gtg ttc cag tac att ggg 1203 Trp Glu Asp CysGln Gln His Arg Val Thr Val Phe Gln Tyr Ile Gly 380 385 390 395 gag ctgtgc cga tac ctt gtc aac cag ccc ccg agc aag gca gaa cgt 1251 Glu Leu CysArg Tyr Leu Val Asn Gln Pro Pro Ser Lys Ala Glu Arg 400 405 410 ggc cataag gtc cgg ctg gca gtg ggc agc ggg ctg cgc cca gat acc 1299 Gly His LysVal Arg Leu Ala Val Gly Ser Gly Leu Arg Pro Asp Thr 415 420 425 tgg gagcgt ttt gtg cgg cgc ttc ggg ccc ctg cag gtg ctg gag aca 1347 Trp Glu ArgPhe Val Arg Arg Phe Gly Pro Leu Gln Val Leu Glu Thr 430 435 440 tat ggactg aca gag ggc aac gtg gcc acc atc aac tac aca gga cag 1395 Tyr Gly LeuThr Glu Gly Asn Val Ala Thr Ile Asn Tyr Thr Gly Gln 445 450 455 cgg ggcgct gtg ggg cgt gct tcc tgg ctt tac aag cat atc ttc ccc 1443 Arg Gly AlaVal Gly Arg Ala Ser Trp Leu Tyr Lys His Ile Phe Pro 460 465 470 475 ttctcc ttg att cgc tat gat gtc acc aca gga gag cca att cgg gac 1491 Phe SerLeu Ile Arg Tyr Asp Val Thr Thr Gly Glu Pro Ile Arg Asp 480 485 490 ccccag ggg cac tgt atg gcc aca tct cca ggt gag cca ggg ctg ctg 1539 Pro GlnGly His Cys Met Ala Thr Ser Pro Gly Glu Pro Gly Leu Leu 495 500 505 gtggcc ccg gta agc cag cag tcc cca ttc ctg ggc tat gct ggc ggg 1587 Val AlaPro Val Ser Gln Gln Ser Pro Phe Leu Gly Tyr Ala Gly Gly 510 515 520 ccagag ctg gcc cag ggg aag ttg cta aag gat gtc ttc cgg cct ggg 1635 Pro GluLeu Ala Gln Gly Lys Leu Leu Lys Asp Val Phe Arg Pro Gly 525 530 535 gatgtt ttc ttc aac act ggg gac ctg ctg gtc tgc gat gac caa ggt 1683 Asp ValPhe Phe Asn Thr Gly Asp Leu Leu Val Cys Asp Asp Gln Gly 540 545 550 555ttt ctc cgc ttc cat gat cgt act gga gac acc ttc agg tgg aag ggg 1731 PheLeu Arg Phe His Asp Arg Thr Gly Asp Thr Phe Arg Trp Lys Gly 560 565 570gag aat gtg gcc aca acc gag gtg gca gag gtc ttc gag gcc cta gat 1779 GluAsn Val Ala Thr Thr Glu Val Ala Glu Val Phe Glu Ala Leu Asp 575 580 585ttt ctt cag gag gtg aac gtc tat gga gtc act gtg cca ggg cat gaa 1827 PheLeu Gln Glu Val Asn Val Tyr Gly Val Thr Val Pro Gly His Glu 590 595 600ggc agg gct gga atg gca gcc cta gtt ctg cgt ccc ccc cac gct ttg 1875 GlyArg Ala Gly Met Ala Ala Leu Val Leu Arg Pro Pro His Ala Leu 605 610 615gac ctt atg cag ctc tac acc cac gtg tct gag aac ttg cca cct tat 1923 AspLeu Met Gln Leu Tyr Thr His Val Ser Glu Asn Leu Pro Pro Tyr 620 625 630635 gcc cgg ccc cga ttc ctc agg ctc cag gag tct ttg gcc acc aca gag 1971Ala Arg Pro Arg Phe Leu Arg Leu Gln Glu Ser Leu Ala Thr Thr Glu 640 645650 acc ttc aaa cag cag aaa gtt cgg atg gca aat gag ggc ttc gac ccc 2019Thr Phe Lys Gln Gln Lys Val Arg Met Ala Asn Glu Gly Phe Asp Pro 655 660665 agc acc ctg tct gac cca ctg tac gtt ctg gac cag gct gta ggt gcc 2067Ser Thr Leu Ser Asp Pro Leu Tyr Val Leu Asp Gln Ala Val Gly Ala 670 675680 tac ctg ccc ctc aca act gcc cgg tac agc gcc ctc ctg gca gga aac 2115Tyr Leu Pro Leu Thr Thr Ala Arg Tyr Ser Ala Leu Leu Ala Gly Asn 685 690695 ctt cga atc tgagaacttc cacacctgag gcacctgaga gaggaactct 2164 Leu ArgIle 700 gt 2166 <210> SEQ ID NO 102 <211> LENGTH: 702 <212> TYPE: PRT<213> ORGANISM: Homo sapiens <400> SEQUENCE: 102 Met Phe Ala Ser Gly TrpAsn Gln Thr Val Pro Ile Glu Glu Ala Gly 1 5 10 15 Ser Met Ala Ala LeuLeu Leu Leu Pro Leu Leu Leu Leu Leu Pro Leu 20 25 30 Leu Leu Leu Leu LysLeu His Leu Trp Pro Gln Leu Arg Trp Leu Pro 35 40 45 Ala Asp Leu Ala PheAla Val Arg Ala Leu Cys Cys Lys Arg Ala Leu 50 55 60 Arg Ala Arg Ala LeuAla Ala Ala Ala Ala Asp Pro Glu Gly Pro Glu 65 70 75 80 Gly Gly Cys SerLeu Ala Trp Arg Leu Ala Glu Leu Ala Gln Gln Arg 85 90 95 Ala Ala His ThrPhe Leu Ile His Gly Ser Arg Arg Phe Ser Tyr Ser 100 105 110 Glu Ala GluArg Glu Ser Asn Arg Ala Ala Arg Ala Phe Leu Arg Ala 115 120 125 Leu GlyTrp Asp Trp Gly Pro Asp Gly Gly Asp Ser Gly Glu Gly Ser 130 135 140 AlaGly Glu Gly Glu Arg Ala Ala Pro Gly Ala Gly Asp Ala Ala Ala 145 150 155160 Gly Ser Gly Ala Glu Phe Ala Gly Gly Asp Gly Ala Ala Arg Gly Gly 165170 175 Gly Glu Pro Ala Ala Pro Leu Ser Pro Gly Ala Thr Val Ala Leu Leu180 185 190 Leu Pro Ala Gly Pro Glu Phe Leu Trp Leu Trp Phe Gly Leu AlaLys 195 200 205 Ala Gly Leu Arg Thr Ala Phe Val Pro Thr Ala Leu Arg ArgGly Pro 210 215 220 Leu Leu His Cys Leu Arg Ser Cys Gly Ala Arg Ala LeuVal Leu Ala 225 230 235 240 Pro Glu Phe Leu Glu Ser Leu Glu Pro Asp LeuPro Ala Leu Arg Ala 245 250 255 Met Gly Leu His Leu Trp Ala Ala Gly ProGly Thr His Pro Ala Gly 260 265 270 Ile Ser Asp Leu Leu Ala Glu Val SerAla Glu Val Asp Gly Pro Val 275 280 285 Pro Gly Tyr Leu Ser Ser Pro GlnSer Ile Thr Asp Thr Cys Leu Tyr 290 295 300 Ile Phe Thr Ser Gly Thr ThrGly Leu Pro Lys Ala Ala Arg Ile Ser 305 310 315 320 His Leu Lys Ile LeuGln Cys Gln Gly Phe Tyr Gln Leu Cys Gly Val 325 330 335 His Gln Glu AspVal Ile Tyr Leu Ala Leu Pro Leu Tyr His Met Ser 340 345 350 Gly Ser LeuLeu Gly Ile Val Gly Cys Met Gly Ile Gly Ala Thr Val 355 360 365 Val LeuLys Ser Lys Phe Ser Ala Gly Gln Phe Trp Glu Asp Cys Gln 370 375 380 GlnHis Arg Val Thr Val Phe Gln Tyr Ile Gly Glu Leu Cys Arg Tyr 385 390 395400 Leu Val Asn Gln Pro Pro Ser Lys Ala Glu Arg Gly His Lys Val Arg 405410 415 Leu Ala Val Gly Ser Gly Leu Arg Pro Asp Thr Trp Glu Arg Phe Val420 425 430 Arg Arg Phe Gly Pro Leu Gln Val Leu Glu Thr Tyr Gly Leu ThrGlu 435 440 445 Gly Asn Val Ala Thr Ile Asn Tyr Thr Gly Gln Arg Gly AlaVal Gly 450 455 460 Arg Ala Ser Trp Leu Tyr Lys His Ile Phe Pro Phe SerLeu Ile Arg 465 470 475 480 Tyr Asp Val Thr Thr Gly Glu Pro Ile Arg AspPro Gln Gly His Cys 485 490 495 Met Ala Thr Ser Pro Gly Glu Pro Gly LeuLeu Val Ala Pro Val Ser 500 505 510 Gln Gln Ser Pro Phe Leu Gly Tyr AlaGly Gly Pro Glu Leu Ala Gln 515 520 525 Gly Lys Leu Leu Lys Asp Val PheArg Pro Gly Asp Val Phe Phe Asn 530 535 540 Thr Gly Asp Leu Leu Val CysAsp Asp Gln Gly Phe Leu Arg Phe His 545 550 555 560 Asp Arg Thr Gly AspThr Phe Arg Trp Lys Gly Glu Asn Val Ala Thr 565 570 575 Thr Glu Val AlaGlu Val Phe Glu Ala Leu Asp Phe Leu Gln Glu Val 580 585 590 Asn Val TyrGly Val Thr Val Pro Gly His Glu Gly Arg Ala Gly Met 595 600 605 Ala AlaLeu Val Leu Arg Pro Pro His Ala Leu Asp Leu Met Gln Leu 610 615 620 TyrThr His Val Ser Glu Asn Leu Pro Pro Tyr Ala Arg Pro Arg Phe 625 630 635640 Leu Arg Leu Gln Glu Ser Leu Ala Thr Thr Glu Thr Phe Lys Gln Gln 645650 655 Lys Val Arg Met Ala Asn Glu Gly Phe Asp Pro Ser Thr Leu Ser Asp660 665 670 Pro Leu Tyr Val Leu Asp Gln Ala Val Gly Ala Tyr Leu Pro LeuThr 675 680 685 Thr Ala Arg Tyr Ser Ala Leu Leu Ala Gly Asn Leu Arg Ile690 695 700 <210> SEQ ID NO 103 <211> LENGTH: 19 <212> TYPE: DNA <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Oligonucleotide <400> SEQUENCE: 103 cccccaccag agaggctcc 19 <210> SEQ IDNO 104 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: Oligonucleotide <400>SEQUENCE: 104 ccacccccgg aaagcctgc 19 <210> SEQ ID NO 105 <211> LENGTH:19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Oligonucleotide <400> SEQUENCE: 105 ggagcctctctggtggggg 19 <210> SEQ ID NO 106 <211> LENGTH: 60 <212> TYPE: DNA <213>ORGANISM: Mus musculus <400> SEQUENCE: 106 gatggctggt ggtgtccaagggggcggggc aggccgggtg atccggctgg gggctggaac 60 <210> SEQ ID NO 107 <211>LENGTH: 59 <212> TYPE: DNA <213> ORGANISM: Mus musculus <220> FEATURE:<221> NAME/KEY: misc_feature <222> LOCATION: (1)...(59) <223> OTHERINFORMATION: n = A,T,C or G <220> FEATURE: <221> NAME/KEY: misc_feature<222> LOCATION: 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33,34,35, 36, 37 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE:107 gatggctggt ggtgtccaan nnnnnnnnnn nnnnnnntga tccggctggg ggctggaac 59<210> SEQ ID NO 108 <211> LENGTH: 60 <212> TYPE: DNA <213> ORGANISM: Musmusculus <400> SEQUENCE: 108 gatggctggt ggtgtccaag ggaacgaggc aggccgggtgatccggctgg gggctggaac 60 <210> SEQ ID NO 109 <211> LENGTH: 61 <212>TYPE: DNA <213> ORGANISM: Mus musculus <400> SEQUENCE: 109 atggctggtggtgtccaagg gggcggggca ggccgggtga tccggctggg ggctggaact 60 g 61 <210> SEQID NO 110 <211> LENGTH: 61 <212> TYPE: DNA <213> ORGANISM: Mus musculus<400> SEQUENCE: 110 taccgaccac cacaggttcc cccgccccgt ccggcccactaggccgaccc ccgaccttga 60 c 61 <210> SEQ ID NO 111 <211> LENGTH: 21 <212>TYPE: DNA <213> ORGANISM: Mus musculus <400> SEQUENCE: 111 gtgtccaagggggcggggca g 21 <210> SEQ ID NO 112 <211> LENGTH: 21 <212> TYPE: DNA<213> ORGANISM: Mus musculus <400> SEQUENCE: 112 cacaggttcc cccgccccgt c21 <210> SEQ ID NO 113 <211> LENGTH: 263 <212> TYPE: DNA <213> ORGANISM:Mus musculus <400> SEQUENCE: 113 gaggatggct ggtggtgtcc aagggggcggggaggccggg tgatccggct gggggctgga 60 actgtagaat tcccagccag taagaactaagtaacaaaag gacagagtcc atgggtcaca 120 ttcagttgct gatagtactt ggtcatatttgggaagtggg tagacagatt tccttaaagg 180 caggtagtta gggctttgga gcactcatcagagctaagag agattacacg ctctcatcta 240 cttcagaaag agccaatgcc atg 263 <210>SEQ ID NO 114 <211> LENGTH: 9 <212> TYPE: DNA <213> ORGANISM: Musmusculus <400> SEQUENCE: 114 ggggcgggg 9 <210> SEQ ID NO 115 <211>LENGTH: 10 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: primer <400> SEQUENCE: 115 ctaacaggag10 <210> SEQ ID NO 116 <211> LENGTH: 2402 <212> TYPE: DNA <213>ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: CDS <222>LOCATION: (51)...(2240) <400> SEQUENCE: 116 cccgggtttc tgctctccgcccgtgtggag tggtgggggc ctgggtggga atg ggc 56 Met Gly 1 gtg tgc cag cgcacg cgc gct ccc tgg aag gag aag tct cag cta gaa 104 Val Cys Gln Arg ThrArg Ala Pro Trp Lys Glu Lys Ser Gln Leu Glu 5 10 15 cga gcg gcc cta ggtttt cgg aag gga gga tca ggg atg ttt gcg agc 152 Arg Ala Ala Leu Gly PheArg Lys Gly Gly Ser Gly Met Phe Ala Ser 20 25 30 ggc tgg aac cag acg gtgccg ata gag gaa gcg ggc tcc atg gct gcc 200 Gly Trp Asn Gln Thr Val ProIle Glu Glu Ala Gly Ser Met Ala Ala 35 40 45 50 ctc ctg ctg ctg ccc ctgctg ctg ttg cta ccg ctg ctg ctg ctg aag 248 Leu Leu Leu Leu Pro Leu LeuLeu Leu Leu Pro Leu Leu Leu Leu Lys 55 60 65 cta cac ctc tgg ccg cag ttgcgc tgg ctt ccg gcg gac ttg gcc ttt 296 Leu His Leu Trp Pro Gln Leu ArgTrp Leu Pro Ala Asp Leu Ala Phe 70 75 80 gcg gtg cga gct ctg tgc tgc aaaagg gct ctt cga gct cgc gcc ctg 344 Ala Val Arg Ala Leu Cys Cys Lys ArgAla Leu Arg Ala Arg Ala Leu 85 90 95 gcc gcg gct gcc gcc gac ccg gaa ggtccc gag ggg ggc tgc agc ctg 392 Ala Ala Ala Ala Ala Asp Pro Glu Gly ProGlu Gly Gly Cys Ser Leu 100 105 110 gcc tgg cgc ctc gcg gaa ctg gcc cagcag cgc gcc gcg cac acc ttt 440 Ala Trp Arg Leu Ala Glu Leu Ala Gln GlnArg Ala Ala His Thr Phe 115 120 125 130 ctc att cac ggc tcg cgg cgc tttagc tac tca gag gcg gag cgc gag 488 Leu Ile His Gly Ser Arg Arg Phe SerTyr Ser Glu Ala Glu Arg Glu 135 140 145 agt aac agg gct gca cgc gcc ttccta cgt gcg cta ggc tgg gac tgg 536 Ser Asn Arg Ala Ala Arg Ala Phe LeuArg Ala Leu Gly Trp Asp Trp 150 155 160 gga ccc gac ggc ggc gac agc ggcgag ggg agc gct gga gaa ggc gag 584 Gly Pro Asp Gly Gly Asp Ser Gly GluGly Ser Ala Gly Glu Gly Glu 165 170 175 cgg gca gcg ccg gga gcc gga gatgca gcg gcc gga agc ggc gcg gag 632 Arg Ala Ala Pro Gly Ala Gly Asp AlaAla Ala Gly Ser Gly Ala Glu 180 185 190 ttt gcc gga ggg gac ggt gcc gccaga ggt gga gga gcc gcc gcc cct 680 Phe Ala Gly Gly Asp Gly Ala Ala ArgGly Gly Gly Ala Ala Ala Pro 195 200 205 210 ctg tca cct gga gca act gtggcg ctg ctc ctc ccc gct ggc cca gag 728 Leu Ser Pro Gly Ala Thr Val AlaLeu Leu Leu Pro Ala Gly Pro Glu 215 220 225 ttt ctg tgg ctc tgg ttc gggctg gcc aag gcc ggc ctg cgc act gcc 776 Phe Leu Trp Leu Trp Phe Gly LeuAla Lys Ala Gly Leu Arg Thr Ala 230 235 240 ttt gtg ccc acc gcc ctg cgccgg ggc ccc ctg ctg cac tgc ctc cgc 824 Phe Val Pro Thr Ala Leu Arg ArgGly Pro Leu Leu His Cys Leu Arg 245 250 255 agc tgc ggc gcg cgc gcg ctggtg ctg gcg cca gag ttt ctg gag tcc 872 Ser Cys Gly Ala Arg Ala Leu ValLeu Ala Pro Glu Phe Leu Glu Ser 260 265 270 ctg gag ccg gac ctg ccc gccctg aga gcc atg ggg ctc cac ctg tgg 920 Leu Glu Pro Asp Leu Pro Ala LeuArg Ala Met Gly Leu His Leu Trp 275 280 285 290 gct gca ggc cca gga acccac cct gct gga att agc gat ttg ctg gct 968 Ala Ala Gly Pro Gly Thr HisPro Ala Gly Ile Ser Asp Leu Leu Ala 295 300 305 gaa gtg tcc gct gaa gtggat ggg cca gtg cca gga tac ctc tct tcc 1016 Glu Val Ser Ala Glu Val AspGly Pro Val Pro Gly Tyr Leu Ser Ser 310 315 320 ccc cag agc ata aca gacacg tgc ctg tac atc ttc acc tct ggc acc 1064 Pro Gln Ser Ile Thr Asp ThrCys Leu Tyr Ile Phe Thr Ser Gly Thr 325 330 335 acg ggc ctc ccc aag gctgct cgg atc agt cat ctg aag atc ctg caa 1112 Thr Gly Leu Pro Lys Ala AlaArg Ile Ser His Leu Lys Ile Leu Gln 340 345 350 tgc cag ggc ttc tat cagctg tgt ggt gtc cac cag gaa gat gtg atc 1160 Cys Gln Gly Phe Tyr Gln LeuCys Gly Val His Gln Glu Asp Val Ile 355 360 365 370 tac ctc gcc ctc ccactc tac cac atg tcc ggt tcc ctg ctg ggc atc 1208 Tyr Leu Ala Leu Pro LeuTyr His Met Ser Gly Ser Leu Leu Gly Ile 375 380 385 gtg ggc tgc atg ggcatt ggg gcc aca gtg gtg ctg aaa tcc aag ttc 1256 Val Gly Cys Met Gly IleGly Ala Thr Val Val Leu Lys Ser Lys Phe 390 395 400 tcg gct ggt cag ttctgg gaa gat tgc cag cag cac agg gtg acg gtg 1304 Ser Ala Gly Gln Phe TrpGlu Asp Cys Gln Gln His Arg Val Thr Val 405 410 415 ttc cag tac att ggggag ctg tgc cga tac ctt gtc aac cag ccc ccg 1352 Phe Gln Tyr Ile Gly GluLeu Cys Arg Tyr Leu Val Asn Gln Pro Pro 420 425 430 agc aag gca gaa cgtggc cat aag gtc cgg ctg gca gtg ggc agc ggg 1400 Ser Lys Ala Glu Arg GlyHis Lys Val Arg Leu Ala Val Gly Ser Gly 435 440 445 450 ctg cgc cca gatacc tgg gag cgt ttt gtg cgg cgc ttc ggg ccc ctg 1448 Leu Arg Pro Asp ThrTrp Glu Arg Phe Val Arg Arg Phe Gly Pro Leu 455 460 465 cag gtg ctg gagaca tat gga ctg aca gag ggc aac gtg gcc acc atc 1496 Gln Val Leu Glu ThrTyr Gly Leu Thr Glu Gly Asn Val Ala Thr Ile 470 475 480 aac tac aca ggacag cgg ggc gct gtg ggg cgt gct tcc tgg ctt tac 1544 Asn Tyr Thr Gly GlnArg Gly Ala Val Gly Arg Ala Ser Trp Leu Tyr 485 490 495 aag cat atc ttcccc ttc tcc ttg att cgc tat gat gtc acc aca gga 1592 Lys His Ile Phe ProPhe Ser Leu Ile Arg Tyr Asp Val Thr Thr Gly 500 505 510 gag cca att cgggac ccc cag ggg cac tgt atg gcc aca tct cca ggt 1640 Glu Pro Ile Arg AspPro Gln Gly His Cys Met Ala Thr Ser Pro Gly 515 520 525 530 gag cca gggctg ctg gtg gcc ccg gta agc cag cag tcc cca ttc ctg 1688 Glu Pro Gly LeuLeu Val Ala Pro Val Ser Gln Gln Ser Pro Phe Leu 535 540 545 ggc tat gctggc ggg cca gag ctg gcc cag ggg aag ttg cta aag gat 1736 Gly Tyr Ala GlyGly Pro Glu Leu Ala Gln Gly Lys Leu Leu Lys Asp 550 555 560 gtc ttc cggcct ggg gat gtt ttc ttc aac act ggg gac ctg ctg gtc 1784 Val Phe Arg ProGly Asp Val Phe Phe Asn Thr Gly Asp Leu Leu Val 565 570 575 tgc gat gaccaa ggt ttt ctc cgc ttc cat gat cgt act gga gac acc 1832 Cys Asp Asp GlnGly Phe Leu Arg Phe His Asp Arg Thr Gly Asp Thr 580 585 590 ttc agg tggaag ggg gag aat gtg gcc aca acc gag gtg gca gag gtc 1880 Phe Arg Trp LysGly Glu Asn Val Ala Thr Thr Glu Val Ala Glu Val 595 600 605 610 ttc gaggcc cta gat ttt ctt cag gag gtg aac gtc tat gga gtc act 1928 Phe Glu AlaLeu Asp Phe Leu Gln Glu Val Asn Val Tyr Gly Val Thr 615 620 625 gtg ccaggg cat gaa ggc agg gct gga atg gca gcc cta gtt ctg cgt 1976 Val Pro GlyHis Glu Gly Arg Ala Gly Met Ala Ala Leu Val Leu Arg 630 635 640 ccc ccccac gct ttg gac ctt atg cag ctc tac acc cac gtg tct gag 2024 Pro Pro HisAla Leu Asp Leu Met Gln Leu Tyr Thr His Val Ser Glu 645 650 655 aac ttgcca cct tat gcc cgg ccc cga ttc ctc agg ctc cag gag tct 2072 Asn Leu ProPro Tyr Ala Arg Pro Arg Phe Leu Arg Leu Gln Glu Ser 660 665 670 ttg gccacc aca gag acc ttc aaa cag cag aaa gtt cgg atg gca aat 2120 Leu Ala ThrThr Glu Thr Phe Lys Gln Gln Lys Val Arg Met Ala Asn 675 680 685 690 gagggc ttc gac ccc agc acc ctg tct gac cca ctg tac gtt ctg gac 2168 Glu GlyPhe Asp Pro Ser Thr Leu Ser Asp Pro Leu Tyr Val Leu Asp 695 700 705 caggct gta ggt gcc tac ctg ccc ctc aca act gcc cgg tac agc gcc 2216 Gln AlaVal Gly Ala Tyr Leu Pro Leu Thr Thr Ala Arg Tyr Ser Ala 710 715 720 ctcctg gca gga aac ctt cga atc tgagaacttc cacacctgag gcacctgaga 2270 LeuLeu Ala Gly Asn Leu Arg Ile 725 730 gaggaactct gtggggtggg ggccgttgcaggtgtactgg gctgtcaggg atcttttcta 2330 taccagaact gcggtcacta ttttgtaataaatgtggctg gagctgatcc agctgtctct 2390 gaaaaaaaaa aa 2402 <210> SEQ ID NO117 <211> LENGTH: 730 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400>SEQUENCE: 117 Met Gly Val Cys Gln Arg Thr Arg Ala Pro Trp Lys Glu LysSer Gln 1 5 10 15 Leu Glu Arg Ala Ala Leu Gly Phe Arg Lys Gly Gly SerGly Met Phe 20 25 30 Ala Ser Gly Trp Asn Gln Thr Val Pro Ile Glu Glu AlaGly Ser Met 35 40 45 Ala Ala Leu Leu Leu Leu Pro Leu Leu Leu Leu Leu ProLeu Leu Leu 50 55 60 Leu Lys Leu His Leu Trp Pro Gln Leu Arg Trp Leu ProAla Asp Leu 65 70 75 80 Ala Phe Ala Val Arg Ala Leu Cys Cys Lys Arg AlaLeu Arg Ala Arg 85 90 95 Ala Leu Ala Ala Ala Ala Ala Asp Pro Glu Gly ProGlu Gly Gly Cys 100 105 110 Ser Leu Ala Trp Arg Leu Ala Glu Leu Ala GlnGln Arg Ala Ala His 115 120 125 Thr Phe Leu Ile His Gly Ser Arg Arg PheSer Tyr Ser Glu Ala Glu 130 135 140 Arg Glu Ser Asn Arg Ala Ala Arg AlaPhe Leu Arg Ala Leu Gly Trp 145 150 155 160 Asp Trp Gly Pro Asp Gly GlyAsp Ser Gly Glu Gly Ser Ala Gly Glu 165 170 175 Gly Glu Arg Ala Ala ProGly Ala Gly Asp Ala Ala Ala Gly Ser Gly 180 185 190 Ala Glu Phe Ala GlyGly Asp Gly Ala Ala Arg Gly Gly Gly Ala Ala 195 200 205 Ala Pro Leu SerPro Gly Ala Thr Val Ala Leu Leu Leu Pro Ala Gly 210 215 220 Pro Glu PheLeu Trp Leu Trp Phe Gly Leu Ala Lys Ala Gly Leu Arg 225 230 235 240 ThrAla Phe Val Pro Thr Ala Leu Arg Arg Gly Pro Leu Leu His Cys 245 250 255Leu Arg Ser Cys Gly Ala Arg Ala Leu Val Leu Ala Pro Glu Phe Leu 260 265270 Glu Ser Leu Glu Pro Asp Leu Pro Ala Leu Arg Ala Met Gly Leu His 275280 285 Leu Trp Ala Ala Gly Pro Gly Thr His Pro Ala Gly Ile Ser Asp Leu290 295 300 Leu Ala Glu Val Ser Ala Glu Val Asp Gly Pro Val Pro Gly TyrLeu 305 310 315 320 Ser Ser Pro Gln Ser Ile Thr Asp Thr Cys Leu Tyr IlePhe Thr Ser 325 330 335 Gly Thr Thr Gly Leu Pro Lys Ala Ala Arg Ile SerHis Leu Lys Ile 340 345 350 Leu Gln Cys Gln Gly Phe Tyr Gln Leu Cys GlyVal His Gln Glu Asp 355 360 365 Val Ile Tyr Leu Ala Leu Pro Leu Tyr HisMet Ser Gly Ser Leu Leu 370 375 380 Gly Ile Val Gly Cys Met Gly Ile GlyAla Thr Val Val Leu Lys Ser 385 390 395 400 Lys Phe Ser Ala Gly Gln PheTrp Glu Asp Cys Gln Gln His Arg Val 405 410 415 Thr Val Phe Gln Tyr IleGly Glu Leu Cys Arg Tyr Leu Val Asn Gln 420 425 430 Pro Pro Ser Lys AlaGlu Arg Gly His Lys Val Arg Leu Ala Val Gly 435 440 445 Ser Gly Leu ArgPro Asp Thr Trp Glu Arg Phe Val Arg Arg Phe Gly 450 455 460 Pro Leu GlnVal Leu Glu Thr Tyr Gly Leu Thr Glu Gly Asn Val Ala 465 470 475 480 ThrIle Asn Tyr Thr Gly Gln Arg Gly Ala Val Gly Arg Ala Ser Trp 485 490 495Leu Tyr Lys His Ile Phe Pro Phe Ser Leu Ile Arg Tyr Asp Val Thr 500 505510 Thr Gly Glu Pro Ile Arg Asp Pro Gln Gly His Cys Met Ala Thr Ser 515520 525 Pro Gly Glu Pro Gly Leu Leu Val Ala Pro Val Ser Gln Gln Ser Pro530 535 540 Phe Leu Gly Tyr Ala Gly Gly Pro Glu Leu Ala Gln Gly Lys LeuLeu 545 550 555 560 Lys Asp Val Phe Arg Pro Gly Asp Val Phe Phe Asn ThrGly Asp Leu 565 570 575 Leu Val Cys Asp Asp Gln Gly Phe Leu Arg Phe HisAsp Arg Thr Gly 580 585 590 Asp Thr Phe Arg Trp Lys Gly Glu Asn Val AlaThr Thr Glu Val Ala 595 600 605 Glu Val Phe Glu Ala Leu Asp Phe Leu GlnGlu Val Asn Val Tyr Gly 610 615 620 Val Thr Val Pro Gly His Glu Gly ArgAla Gly Met Ala Ala Leu Val 625 630 635 640 Leu Arg Pro Pro His Ala LeuAsp Leu Met Gln Leu Tyr Thr His Val 645 650 655 Ser Glu Asn Leu Pro ProTyr Ala Arg Pro Arg Phe Leu Arg Leu Gln 660 665 670 Glu Ser Leu Ala ThrThr Glu Thr Phe Lys Gln Gln Lys Val Arg Met 675 680 685 Ala Asn Glu GlyPhe Asp Pro Ser Thr Leu Ser Asp Pro Leu Tyr Val 690 695 700 Leu Asp GlnAla Val Gly Ala Tyr Leu Pro Leu Thr Thr Ala Arg Tyr 705 710 715 720 SerAla Leu Leu Ala Gly Asn Leu Arg Ile 725 730 <210> SEQ ID NO 118 <400>SEQUENCE: 118 000 <210> SEQ ID NO 119 <400> SEQUENCE: 119 000 <210> SEQID NO 120 <211> LENGTH: 89 <212> TYPE: PRT <213> ORGANISM: Mus musculus<400> SEQUENCE: 120 Arg Pro Pro Gln Ala Leu Asn Leu Val Gln Leu Tyr SerHis Val Ser 1 5 10 15 Glu Asn Leu Pro Pro Tyr Ala Arg Pro Arg Phe LeuArg Leu Gln Glu 20 25 30 Ser Leu Ala Thr Thr Glu Thr Phe Lys Gln Gln LysVal Arg Met Ala 35 40 45 Asn Glu Gly Phe Asp Pro Ser Val Leu Ser Asp ProLeu Tyr Val Leu 50 55 60 Asp Gln Asp Ile Gly Ala Tyr Leu Pro Leu Thr ProAla Arg Tyr Ser 65 70 75 80 Ala Leu Leu Ser Gly Asp Leu Arg Ile 85 <210>SEQ ID NO 121 <211> LENGTH: 197 <212> TYPE: PRT <213> ORGANISM: Homosapiens <400> SEQUENCE: 121 Arg Val Phe Ile Lys Thr Ile Arg Arg Asp IlePhe Gly Gly Leu Val 1 5 10 15 Leu Leu Lys Val Lys Ala Lys Val Arg GlnCys Leu Gln Glu Arg Arg 20 25 30 Thr Val Pro Ile Leu Phe Ala Ser Thr ValArg Arg His Pro Asp Lys 35 40 45 Thr Ala Leu Ile Phe Glu Gly Thr Asp ThrHis Trp Thr Phe Arg Gln 50 55 60 Leu Asp Glu Tyr Ser Ser Ser Val Ala AsnPhe Leu Gln Ala Arg Gly 65 70 75 80 Leu Ala Ser Gly Asp Val Ala Ala IlePhe Met Glu Asn Arg Asn Glu 85 90 95 Phe Val Gly Leu Trp Leu Gly Met AlaLys Leu Gly Val Glu Ala Ala 100 105 110 Leu Ile Asn Thr Asn Leu Arg ArgAsp Ala Leu Leu His Cys Leu Thr 115 120 125 Thr Ser Arg Ala Arg Ala LeuVal Phe Gly Ser Glu Met Ala Ser Ala 130 135 140 Ile Cys Glu Val His AlaSer Leu Asp Pro Ser Leu Ser Leu Phe Cys 145 150 155 160 Ser Gly Ser TrpGlu Pro Gly Ala Val Pro Pro Ser Thr Glu His Leu 165 170 175 Asp Pro LeuLeu Lys Asp Ala Pro Lys His Leu Pro Ser Cys Pro Asp 180 185 190 Lys GlyPhe Thr Asp 195 <210> SEQ ID NO 122 <211> LENGTH: 248 <212> TYPE: PRT<213> ORGANISM: Homo sapiens <400> SEQUENCE: 122 Arg Val Phe Ile Lys ThrIle Arg Arg Asp Ile Phe Gly Gly Leu Val 1 5 10 15 Leu Leu Lys Val LysAla Lys Val Arg Gln Cys Leu Gln Glu Arg Arg 20 25 30 Thr Val Pro Ile LeuPhe Ala Ser Thr Val Arg Arg His Pro Asp Lys 35 40 45 Thr Ala Leu Ile PheGlu Gly Thr Asp Thr His Trp Thr Phe Arg Gln 50 55 60 Leu Asp Glu Tyr SerSer Ser Val Ala Asn Phe Leu Gln Ala Arg Gly 65 70 75 80 Leu Ala Ser GlyAsp Val Ala Ala Ile Phe Met Glu Asn Arg Asn Glu 85 90 95 Phe Val Gly LeuTrp Leu Gly Met Ala Lys Leu Gly Val Glu Ala Ala 100 105 110 Leu Ile AsnThr Asn Leu Arg Arg Asp Ala Leu Leu His Cys Leu Thr 115 120 125 Thr SerArg Ala Arg Ala Leu Val Phe Gly Ser Glu Met Ala Ser Ala 130 135 140 IleCys Glu Val His Ala Ser Leu Asp Pro Ser Leu Ser Leu Phe Cys 145 150 155160 Ser Gly Ser Trp Glu Pro Gly Ala Val Pro Pro Ser Thr Glu His Leu 165170 175 Asp Pro Leu Leu Lys Asp Ala Pro Lys His Leu Pro Ser Cys Pro Asp180 185 190 Lys Gly Phe Thr Asp Lys Leu Phe Tyr Ile Tyr Thr Ser Gly ThrThr 195 200 205 Gly Leu Pro Lys Ala Ala Ile Val Val His Ser Arg Tyr TyrArg Met 210 215 220 Ala Ala Leu Val Tyr Tyr Gly Phe Arg Met Arg Pro AsnAsp Ile Val 225 230 235 240 Tyr Asp Cys Leu Pro Leu Tyr His 245 <210>SEQ ID NO 123 <211> LENGTH: 165 <212> TYPE: PRT <213> ORGANISM: Homosapiens <400> SEQUENCE: 123 Gly Asp Val Ala Ala Ile Phe Met Glu Asn ArgAsn Glu Phe Val Gly 1 5 10 15 Leu Trp Leu Gly Met Ala Lys Leu Gly ValGlu Ala Ala Leu Ile Asn 20 25 30 Thr Asn Leu Arg Arg Asp Ala Leu Leu HisCys Leu Thr Thr Ser Arg 35 40 45 Ala Arg Ala Leu Val Phe Gly Ser Glu MetAla Ser Ala Ile Cys Glu 50 55 60 Val His Ala Ser Leu Asp Pro Ser Leu SerLeu Phe Cys Ser Gly Ser 65 70 75 80 Trp Glu Pro Gly Ala Val Pro Pro SerThr Glu His Leu Asp Pro Leu 85 90 95 Leu Lys Asp Ala Pro Lys His Leu ProSer Cys Pro Asp Lys Gly Phe 100 105 110 Thr Asp Lys Leu Phe Tyr Ile TyrThr Ser Gly Thr Thr Gly Leu Pro 115 120 125 Lys Ala Ala Ile Val Val HisSer Arg Tyr Tyr Arg Met Ala Ala Leu 130 135 140 Val Tyr Tyr Gly Phe ArgMet Arg Pro Asn Asp Ile Val Tyr Asp Cys 145 150 155 160 Leu Pro Leu TyrHis 165 <210> SEQ ID NO 124 <211> LENGTH: 227 <212> TYPE: PRT <213>ORGANISM: Homo sapiens <400> SEQUENCE: 124 Arg Leu Val Arg Val Asn GluAsp Thr Met Glu Leu Ile Arg Gly Pro 1 5 10 15 Asp Gly Val Cys Ile ProCys Gln Pro Gly Glu Pro Gly Gln Leu Val 20 25 30 Gly Arg Ile Ile Gln LysAsp Pro Leu Arg Arg Phe Asp Gly Tyr Leu 35 40 45 Asn Gln Gly Ala Asn AsnLys Lys Ile Ala Lys Asp Val Phe Lys Lys 50 55 60 Gly Asp Gln Ala Tyr LeuThr Gly Asp Val Leu Val Met Asp Glu Leu 65 70 75 80 Gly Tyr Leu Tyr PheArg Asp Arg Thr Gly Asp Thr Phe Arg Trp Lys 85 90 95 Gly Glu Asn Val SerThr Thr Glu Val Glu Gly Thr Leu Ser Arg Leu 100 105 110 Leu Asp Met AlaAsp Val Ala Val Tyr Gly Val Glu Val Pro Gly Thr 115 120 125 Glu Gly ArgAla Gly Met Ala Ala Val Ala Ser Pro Thr Gly Asn Cys 130 135 140 Asp LeuGlu Arg Phe Ala Gln Val Leu Glu Lys Glu Leu Pro Leu Tyr 145 150 155 160Ala Arg Pro Ile Phe Leu Arg Leu Leu Pro Glu Leu His Lys Thr Gly 165 170175 Thr Tyr Lys Phe Gln Lys Thr Glu Leu Arg Lys Glu Gly Phe Asp Pro 180185 190 Ala Ile Val Lys Asp Pro Leu Phe Tyr Leu Asp Ala Gln Lys Gly Arg195 200 205 Tyr Val Pro Leu Asp Gln Glu Ala Tyr Ser Arg Ile Gln Ala GlyGlu 210 215 220 Glu Lys Leu 225 <210> SEQ ID NO 125 <211> LENGTH: 41<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Lipocalin signature sequence <220> FEATURE: <221>NAME/KEY: VARIANT <222> LOCATION: (1)...(41) <223> OTHER INFORMATION:Xaa = Any Amino Acid <220> FEATURE: <221> NAME/KEY: VARIANT <222>LOCATION: 5, 16, 17, 41 <223> OTHER INFORMATION: Xaa = Any Amino Acid<400> SEQUENCE: 125 Asp Glu Asn Gly Xaa Asp Glu Asn Gln Gly Ser Thr AlaArg Lys Xaa 1 5 10 15 Xaa Asp Glu Asn Gln Ala Arg Lys Leu Ile Val PheTyr Cys Pro Gly 20 25 30 Cys Trp Phe Tyr Trp Leu Arg His Xaa 35 40 <210>SEQ ID NO 126 <211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM: Homosapiens <400> SEQUENCE: 126 Ser Asn Glu Pro Asp Phe Val His Val Trp PheGly Leu 1 5 10 <210> SEQ ID NO 127 <211> LENGTH: 13 <212> TYPE: PRT<213> ORGANISM: Homo sapiens <400> SEQUENCE: 127 Gly Asn Glu Pro Ala TyrVal Trp Leu Trp Leu Gly Leu 1 5 10 <210> SEQ ID NO 128 <211> LENGTH: 13<212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 128 Pro AlaGly Pro Glu Phe Leu Trp Leu Trp Phe Gly Leu 1 5 10 <210> SEQ ID NO 129<211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400>SEQUENCE: 129 Leu Ala Ser Gln Ala Val Pro Ala Leu Cys Met Trp Leu GlyLeu 1 5 10 15 <210> SEQ ID NO 130 <211> LENGTH: 13 <212> TYPE: PRT <213>ORGANISM: Homo sapiens <400> SEQUENCE: 130 Glu Asn Arg Asn Glu Phe ValGly Leu Trp Leu Gly Met 1 5 10 <210> SEQ ID NO 131 <211> LENGTH: 13<212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 131 Glu GlyArg Pro Glu Phe Val Gly Leu Trp Leu Gly Leu 1 5 10 <210> SEQ ID NO 132<211> LENGTH: 20 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400>SEQUENCE: 132 Cys Leu Tyr Ile Phe Thr Ser Gly Thr Thr Gly Leu Pro LysAla Ala 1 5 10 15 Val Ile Ser Gln 20 <210> SEQ ID NO 133 <211> LENGTH:20 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 133 AlaLeu Tyr Ile Tyr Thr Ser Gly Thr Thr Gly Leu Pro Lys Ala Ala 1 5 10 15Met Ile Thr His 20 <210> SEQ ID NO 134 <211> LENGTH: 20 <212> TYPE: PRT<213> ORGANISM: Homo sapiens <400> SEQUENCE: 134 Cys Leu Tyr Ile Phe ThrSer Gly Thr Thr Gly Leu Pro Lys Ala Ala 1 5 10 15 Arg Ile Ser His 20<210> SEQ ID NO 135 <211> LENGTH: 20 <212> TYPE: PRT <213> ORGANISM:Homo sapiens <400> SEQUENCE: 135 Ala Leu Phe Ile Tyr Thr Ser Gly Thr ThrGly Leu Pro Lys Pro Ala 1 5 10 15 Ile Leu Thr His 20 <210> SEQ ID NO 136<211> LENGTH: 20 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400>SEQUENCE: 136 Leu Phe Tyr Ile Tyr Thr Ser Gly Thr Thr Gly Leu Pro LysAla Ala 1 5 10 15 Ile Val Val His 20 <210> SEQ ID NO 137 <211> LENGTH:20 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 137 LeuPhe Tyr Ile Tyr Thr Ser Gly Thr Thr Gly Leu Pro Lys Ala Ala 1 5 10 15Ile Val Val His 20 <210> SEQ ID NO 138 <211> LENGTH: 36 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: consensus sequence <400> SEQUENCE: 138 Ala Ala Thr Gly AlaGly Cys Cys Gly Gly Ala Cys Thr Thr Cys Gly 1 5 10 15 Thr Thr Cys AlaCys Gly Thr Gly Thr Gly Gly Thr Thr Cys Gly Gly 20 25 30 Cys Cys Thr Cys35 <210> SEQ ID NO 139 <211> LENGTH: 39 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: consensussequence <400> SEQUENCE: 139 Thr Cys Cys Cys Ala Gly Gly Cys Cys Gly ThrThr Cys Cys Ala Gly 1 5 10 15 Cys Cys Cys Thr Gly Thr Gly Thr Ala ThrGly Thr Gly Gly Cys Thr 20 25 30 Gly Gly Gly Gly Cys Thr Gly 35 <210>SEQ ID NO 140 <211> LENGTH: 42 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: consensussequence <400> SEQUENCE: 140 Cys Thr Cys Cys Cys Cys Gly Cys Thr Gly GlyCys Cys Cys Ala Gly 1 5 10 15 Ala Gly Thr Thr Thr Cys Thr Gly Thr GlyGly Cys Thr Cys Thr Gly 20 25 30 Gly Thr Thr Cys Gly Gly Gly Cys Thr Gly35 40

What is claimed is:
 1. An isolated nucleic acid comprising thenucleotide sequence of SEQ ID NO.:116 or its complement.
 2. An isolatednucleic acid comprising the coding sequence of SEQ ID NO.:
 116. 3. Anisolated nucleic acid which encodes a polypeptide comprising the aminoacid sequence of SEQ ID NO.:117 or its complement.
 4. An isolatednucleic acid which hybridizes under stringency conditions of 6× SSC at65° C., followed by at least one wash in 0.2× SSC/0.5% SDS at 65° C., tothe nucleic acid comprising the nucleotide sequence of SEQ ID NO.: 116.5. An isolated nucleic acid consisting of a nucleotide sequence havingat least 95% identity to a nucleotide sequence of claim
 1. 6. Anisolated nucleic acid consisting of a nucleotide sequence having atleast 90% identity to a nucleotide sequence of claim
 1. 7. An isolatednucleic acid encoding a fusion polypeptide, wherein the isolated nucleicacid comprises a nucleotide sequence of SEQ ID NO.:116.
 8. A vectorcomprising a nucleic acid of claim
 1. 9. A vector comprising a nucleicacid of claim
 2. 10. A vector comprising a nucleic acid of claim
 3. 11.A vector comprising a nucleic acid of claim
 4. 12. A vector comprising anucleic acid of claim
 5. 13. A vector comprising a nucleic acid of claim6.
 14. A vector comprising a nucleic acid of claim
 7. 15. An isolatedhost cell transfected with the vector of claim
 8. 16. An isolated hostcell transfected with the vector of claim
 9. 17. An isolated host celltransfected with the vector of claim
 10. 18. An isolated host celltransfected with the vector of claim
 11. 19. An isolated host celltransfected with the vector of claim
 12. 20. An isolated host celltransfected with the vector of claim
 13. 21. An isolated host celltransfected with the vector of claim
 14. 22. A method of producing apolypeptide comprising the step of culturing the host cell of claim 15under conditions in which the nucleic acid is expressed, therebyproducing the polypeptide.
 23. A method of producing a polypeptidecomprising the step of culturing the host cell of claim 16 underconditions in which the nucleic acid is expressed, thereby producing thepolypeptide.
 24. A method of producing a polypeptide comprising the stepof culturing the host cell of claim 17 under conditions in which thenucleic acid is expressed, thereby producing the polypeptide.
 25. Amethod of producing a polypeptide comprising the step of culturing thehost cell of claim 18 under conditions in which the nucleic acid isexpressed, thereby producing the polypeptide.
 26. A method of producinga polypeptide comprising the step of culturing the host cell of claim 19under conditions in which the nucleic acid is expressed, therebyproducing the polypeptide.
 27. A method of producing a polypeptidecomprising the step of culturing the host cell of claim 20 underconditions in which the nucleic acid is expressed, thereby producing thepolypeptide.
 28. A method of producing a polypeptide comprising the stepof culturing the host cell of claim 21 under conditions in which thenucleic acid is expressed, thereby producing the polypeptide.
 29. Anisolated nucleic acid comprising at least 30 contiguous nucleotides ofthe nucleotide sequence of SEQ ID NO.:116.
 30. An isolated nucleic acidcomprising at least 200 contiguous nucleotides of the nucleotidesequence of SEQ ID NO. :116.
 31. An isolated polypeptide comprising theamino acid sequence of SEQ ID NO. :117.
 32. An isolated naturallyoccurring allelic variant of a polypeptide consisting of the amino acidsequence of claim
 31. 33. An isolated polypeptide consisting of an aminoacid sequence having at least 95% identity to the amino acid sequence ofclaim
 31. 34. An isolated polypeptide consisting of an amino acidsequence having at least 90% identity to the amino acid sequence ofclaim
 31. 35. An isolated polypeptide encoded by a nucleic acid thathybridizes to a nucleic acid consisting of the nucleotide sequence ofSEQ ID NO.:117 under stringency conditions of 6× SSC at 65° C., followedby at least two washes in 0.2× SSC/0.5% SDS at 65° C.
 36. A fusionprotein comprising a polypeptide consisting of the amino acid sequenceof SEQ ID NO.:117.
 37. The fusion protein of claim 36, wherein thefusion protein transports fatty acids across a cell membrane or anartificial cell membrane system.
 38. An isolated polypeptide comprisingat least 15 contiguous amino acid residues of SEQID NO.:117.
 39. Anisolated polypeptide comprising at least 50 contiguous amino acidresidues of SEQ ID NO.:117.
 40. An isolated polypeptide comprising atleast 360 contiguous amino acid residues of SEQ ID NO.:117.
 41. Anisolated polypeptide comprising an amino acid sequence having at least15 contiguous amino acid residues of SEQ ID NO.:117, wherein theisolated polypeptide transports fatty acids across a cell membrane or anartificial cell membrane.
 42. An isolated polypeptide encoded by anucleic acid that hybridizes to a nucleic acid consisting of thenucleotide sequence of SEQ ID NO.:116 under stringency conditions of 6×SSC at 65° C., followed by at least two washes in 0.2× SSC/0.5% SDS at65° C.
 43. A method for identifying an agent which binds to a proteincomprising an amino acid sequence of SEQ ID NO.:117 comprising the stepsof contacting the agent with the isolated protein under conditionsappropriate for binding of the agent to the isolated protein, anddetecting a resulting agent-protein complex.
 44. An agent identified bythe method of claim
 43. 45. A method for identifying an agent which isan inhibitor of fatty acid uptake by a protein encoded by apolynucleotide comprising a nucleotide sequence which encodes a proteinconsisting of the amino acid sequence of SEQ ID NO.:1 17, comprising thesteps of: a) maintaining test cells expressing said polynucleotide inthe presence of a fatty acid and an agent to be tested as an inhibitorof fatty acid, uptake; b) measuring uptake of the fatty acid in the testcells; and c) comparing uptake of the fatty acid in the test cells withuptake of the fatty acid in suitable control cells; wherein lower uptakeof the fatty acid in the test cells compared to uptake of the fatty acidin the control cells is indicative that the agent is an inhibitor offatty acid uptake by said protein.
 46. An inhibitor of fatty acid uptakeidentified by the method of claim
 45. 47. The method of claim 45 furthercomprising the steps of: a) administering the agent to one or more testanimals; b) measuring exogenously supplied fatty acids in one or moresamples of tissue or bodily fluid from said test animals; c) measuringexogenously supplied fatty acids in one or more comparable samples oftissue or bodily fluid from suitable control animals; d) comparing thefatty acids of b) with the fatty acids of c); whereby, lower fatty acidsin step b) than in step c) is indicative that the agent is an inhibitorof said protein.
 48. An inhibitor of fatty acid uptake identified by themethod of claim
 47. 49. The method of claim 45, wherein the nucleotidesequence which encodes a protein consists of a nucleotide sequence with95% identity to a nucleotide sequence which encodes the polypeptide withSEQ ID NO.:
 117. 50. A method for identifying an agent which is aninhibitor of a protein encoded by a polynucleotide comprising anucleotide sequence which encodes a protein comprising the amino acidsequence in SEQ ID NO.: 117 comprising the steps of: (a) introducinginto host cells one or more vectors comprising a polynucleotideexpressing said protein; (b) culturing a first aliquot of the host cellswith fatty acid substrate of said protein and with an agent being testedas an inhibitor of said protein; (c) culturing a second aliquot of thehost cells with fatty acid substrate of said protein; (d) measuring, inthe first and second aliquots, uptake of the fatty acid substrate of thehost cells; wherein less uptake of the fatty acid substrate in the firstaliquot compared to the second aliquot is indicative that the agent isan inhibitor of said protein.
 51. An inhibitor of fatty acid uptakeidentified by the method of claim
 52. 52. The method of claim 50 furthercomprising the steps of: a) administering the agent to one or more testanimals; b) measuring exogenously supplied fatty acids in one or moresamples of tissue or bodily fluid from suitable control animals; c)measuring exogenously supplied fatty acids in one or more comparablesamples of tissue or bodily fluid from suitable control animals; and d)comparing the fatty acids of b) with the fatty acids of c), whereby,lower fatty acids in step b) than in step c) is indicative that theagent is an inhibitor of said protein.
 53. A method for identifying anagent which binds to a protein comprising an amino acid sequence of SEQID NO.:1 17 comprising the steps of contacting the agent with theisolated protein under conditions appropriate for binding of the agentto the isolated protein, and detecting a resulting agent-proteincomplex.
 54. A method for identifying an agent which inhibitsinteraction between an isolated protein comprising an amino acidsequence of SEQ ID NO.:117, and further comprising a ligand of saidprotein, comprising: (a) combining: (1) said isolated protein; (2) theligand of said protein; and (3) a candidate agent to be assessed for itsability to inhibit interaction between said protein of (1) and theligand of (2), under conditions appropriate for interaction between thesaid protein of (1) and the ligand of (2); (b) determining the extent towhich said protein of (1) and the ligand of (2) interact; and (c)comparing the extent determined in (b) with the extent to whichinteraction of said protein of (1) and the ligand of (2) occurs in theabsence of the candidate agent to be assessed and under the sameconditions appropriate for interaction of said protein of (1) with theligand of (2); wherein if the extent to which interaction of saidprotein of (1) and the ligand of (2) occurs is less in the presence ofthe candidate agent than in the absence of the candidate agent, thecandidate agent is an agent which inhibits interaction between saidprotein and the ligand of said protein.
 55. A method for detecting, in asample of cells, a nucleic acid molecule consisting of a nucleotidesequence with at least 90% sequence identity to SEQ ID NO.: 116,comprising: a) purifying nucleic acid from the cells; b) hybridizing 1)purified nucleic acid from the cells to 2) purified nucleic acidcomprising SEQ ID NO.:116, under conditions that allow hybridizationbetween 1) and 2) if the sequences of 1) and 2) have at least 90%sequence identity; and c) detecting resulting hybrid nucleic acids inthe hybridization; wherein, if hybrid nucleic acids are detected at asignificant level compared to a suitable control hybridization, then anucleic acid molecule comprising at least 90% sequence identity to SEQID NO: 116, has been detected.
 56. A method for identifying (1) nucleicacid molecules in fixed cells which specifically interact with a (2)nucleic acid molecule comprising the nucleotide sequence in SEQ IDNO.:116, said method comprising the steps of: a) adding to the fixedcells the nucleic acid molecule comprising a nucleotide sequence in SEQID NO.:116; b) incubating the fixed cells under conditions allowinghybridization of (1) with (2); c) removing the nucleic acid molecule ofstep a) that has not hybridized; and d) detecting hybrid moleculescomprising (1) and (2).
 57. A method for detecting FATP3 in a sample ofcells, comprising the steps of adding an agent that specifically bindsto FATP3 to the sample, and detecting agent specifically bound to theFATP3.
 58. The method of claim 57 wherein the agent is an antibody whichbinds to FATP3.
 59. A method for detecting FATP3 in a sample of celllysate, comprising the steps of adding an agent that specifically bindsto FATP3 or FATP4 to the sample, and detecting agent specifically boundto the FATP3 or FATP4.
 60. The method of claim 59 wherein the agent isan antibody which binds to FATP3.
 61. An isolated antibody which bindsto a polypeptide having an amino acid sequence consisting of at least95% amino acid sequence identity with the amino acid sequence of SEQ IDNO.:117.
 62. An isolated antibody which binds to a fatty acid transportprotein having the amino acid sequence of SEQ ID NO.:117.
 63. A methodfor detecting, in a sample of cells, a nucleic acid molecule comprisingat least 90% sequence identity to SEQ ID NO.:116 comprising: a)purifying nucleic acid from the cells; b) hybridizing 1) purifiednucleic acid from the cells to 2) purified nucleic acid comprising SEQID NO.:116 or SEQ ID NO.:52, under conditions that allow hybridizationbetween 1) and 2) if the sequences of 1) and 2) have at least 90%sequence identity; and c) detecting resulting hybrid nucleic acids inthe hybridization; wherein, if hybrid nucleic acids are detected at asignificant level compared to a suitable control hybridization, then anucleic acid molecule having at least 90% sequence identity to SEQ IDNO.:116 or SEQ ID NO.:52, has been detected.
 64. A method for detecting,in a sample of purified nucleic acid, a nucleic acid molecule comprisingat least 90% sequence identity to SEQ ID NO.: 116 comprising: a)hybridizing 1) the sample of purified nucleic acid to 2) purifiednucleic acid comprising SEQ ID NO.:116 or SEQ ID NO.:52, underconditions that allow hybridization between 1) and 2) if the sequencesof 1) and 2) have at least 90% sequence identity; and b) detectingresulting hybrid nucleic acids in the hybridization; wherein, if hybridnucleic acids are detected at a significant level compared to a suitablecontrol hybridization, then a nucleic acid molecule having at least 90%sequence identity to SEQ ID NO.:116 or SEQ ID NO.:52, has been detected.65. A method for detecting FATP3 in a sample of cells, comprising thesteps of adding an agent that specifically binds to FATP3 to the sample,and detecting agent specifically bound to the FATP3.
 66. The method ofclaim 65 wherein the agent is an antibody which binds to FATP3.
 67. Avector comprising a FATP regulatory sequence and at least one targetingsequence directed to the regulatory region of a nucleic acid with anucleotide sequence selected from the group consisting of: a) SEQ IDNO.:46 b) SEQ ID NO.:48 c) SEQ ID NO.:116 d) SEQ ID NO.:52 e) SEQ IDNO.:54 and f) SEQ ID NO.:56
 68. An isolated host cell transfected with avector of claim
 67. 69. A method of producing a polypeptide comprisingculturing the host cell of claim 68 under conditions in which thenucleic acid is expressed, thereby producing the polypeptide.
 70. Anisolated nucleic acid comprising a nucleotide sequence encoding afunctional portion of a FATP polypeptide comprising a lipocalin domain.71. The isolated nucleic acid of claim 70 further comprising anucleotide sequence encoding upstream amino acid residues.
 72. Anisolated nucleic acid comprising a nucleotide sequence encoding aportion of a FATP protein containing a lipocalin domain, wherein thenucleotide sequence is selected from the group consisting of portionsof: a) SEQ ID NO.:46 b) SEQ ID NO.:48 c) SEQ ID NO.:116 d) SEQ ID NO.:52e) SEQ ID NO.:54 and f) SEQ ID NO.:56.
 73. An isolated nucleic acid ofclaim 72 further comprising at least about 90 nucleotides of thesequence upstream of the lipocalin domain.
 74. A vector comprising anucleic acid of claim
 73. 75. An isolated host cell comprising thevector of claim
 74. 76. A method of producing a polypeptide comprisingthe step of culturing the host cell of claim 75 under conditions inwhich the nucleic acid is expressed, thereby producing the polypeptide.77. A functional portion of a FATP polypeptide comprising a lipocalindomain.
 78. The FATP polypeptide of claim 77 further comprising upstreamamino acid residues.
 79. An isolated polypeptide comprising an aminoacid sequence containing a FATP lipocalin domain, wherein the amino acidsequence is selected from the group consisting of portions of: a) SEQ IDNO.:47; b) SEQ ID NO.:49; c) SEQ ID NO.:117; d) SEQ ID NO.:53; e) SEQ IDNO.:55; and f) SEQ ID NO.:57.
 80. A functional portion of a FATPpolypeptide comprising an amino acid sequence selected from the groupconsisting of: a) SEQ ID NO.:126; b) SEQ ID NO.:127; c) SEQ ID NO.:128;d) SEQ ID NO.:129; e) SEQ ID NO.:130; and f) SEQ ID NO.:131.
 81. Afusion protein comprising a polypeptide consisting of a FATP polypeptidecontaining a lipocalin domain.
 82. The fusion protein of claim 81further comprising upstream sequences.
 83. The fusion protein of claim82, wherein the upstream sequences comprise at least about 30 amino acidresidues of an upstream sequence.
 84. A fusion protein comprising apolypeptide consisting of a FATP polypeptide containing a lipocalindomain, wherein the polypeptide consists of an amino acid sequenceselected from the group consisting of portions of: a) SEQ ID NO.:47; b)SEQ ID NO.:49; c) SEQ ID NO.:117; d) SEQ ID NO.:53; e) SEQ ID NO.:55;and f) SEQ ID NO.:57.
 85. The fusion protein of claim 84 furthercomprising upstream sequences.
 86. A method for identifying an agentwhich binds to a polypeptide, wherein the polypeptide comprises a FATPlipocalin domain, comprising the steps of contacting the agent with thepolypeptide under conditions appropriate for binding of the agent to thepolypeptide, and detecting a resulting agent-polypeptide complex. 87.The agent identified by the method of claim
 86. 88. A method foridentifying an agent which binds to a polypeptide, wherein thepolypeptide comprises a FATP lipocalin domain and about 30 amino acidresidues of an upstream sequence, comprising the steps of contacting theagent with the polypeptide under conditions appropriate for binding ofthe agent to the polypeptide, and detecting a resultingagent-polypeptide complex.
 89. The agent identified by the method ofclaim
 88. 90. A method for identifying an agent which binds to apolypeptide, wherein the polypeptide comprises a FATP lipocalin domainand consists of an amino acid sequence selected from the groupconsisting of portions of: a) SEQ ID NO.:47; b) SEQ ID NO.:49; c) SEQ IDNO.:117; d) SEQ ID NO.:53; e) SEQ ID NO.:55; and f) SEQ ID NO.:57,comprising the steps of contacting the agent with the polypeptide underconditions appropriate for binding of the agent to the polypeptide, anddetecting a resulting agent-polypeptide complex.
 91. An agent identifiedby the method of claim
 90. 92. A method for identifying an agent whichbinds to a polypeptide, wherein the polypeptide comprises an amino acidsequence selected from the group consisting of: a) SEQ ID NO.:126; b)SEQ ID NO.:127; c) SEQ ID NO.:128; d) SEQ ID NO.:129; e) SEQ ID NO.:130;and f) SEQ ID NO.:131, comprising the steps of contacting the agent withthe polypeptide under conditions appropriate for binding of the agent tothe polypeptide, and detecting a resulting agent-polypeptide complex.93. An agent identified by the method of claim
 92. 94. A method foridentifying an agent which binds to a polypeptide comprising a FATPlipocalin domain, wherein the polypeptide is encoded by a nucleotidesequence consisting of portions of: a) SEQ ID NO.:46; b) SEQ ID NO.:48;c) SEQ ID NO.:116; d) SEQ ID NO.:52; e) SEQ ID NO.:54; and f) SEQ IDNO.:56. comprising the steps of contacting the agent with thepolypeptide under conditions appropriate for binding of the agent to thepolypeptide, and detecting a resulting agent-polypeptide complex.
 95. Anagent identified by the method of claim
 94. 96. A method for identifyingan agent which binds to a polypeptide comprising a FATP lipocalin domainand upstream sequences, wherein the polypeptide is encoded by anucleotide sequence consisting of portions of:
 1. SEQ ID NO.:46;
 2. SEQID NO.:48;
 3. SEQ ID NO.:116;
 4. SEQ ID NO.:52;
 5. SEQ ID NO.:54; and 6.SEQ ID NO.:56. comprising the steps of contacting the agent with thepolypeptide under conditions appropriate for binding of the agent to thepolypeptide, and detecting a resulting agent-polypeptide complex.
 97. Anagent identified by the method of claim 96.